Cb1 modulator compounds

ABSTRACT

Novel compounds of structural formula (I) are disclosed. As modulators of the Cannabinoid-1 (CB1) receptor, these compounds are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. As such, compounds of the present invention are useful as in the treatment, prevention and suppression of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders (e.g., multiple sclerosis, Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis), cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson&#39;s disease, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith.

BACKGROUND OF THE INVENTION

Marijuana (Cannabis satiha L.) and its derivatives have been used forcenturies for medicinal and recreational purposes. A major activeingredient in marijuana and hashish has been determined to beΔ⁹-tetrahydrocannabinol (Δ⁹-THC). Detailed research has revealed thatthe biological action of Δ⁹-THC and other members of the cannabinoidfamily occurs through two G-protein coupled receptors termed CB₁ andCB₂. The CB₁ receptor is primarily found in the central and peripheralnervous systems and to a lesser extent in several peripheral organs. TheCB₂ receptor is found primarily in lymphoid tissues and cells. Threeendogenous ligands for the cannabinoid receptors derived fromarachidonic acid have been identified (anandamide, 2-arachidonoylglycerol, and 2-arachidonyl glycerol ether). Each is an agonist withactivities similar to Δ⁹-THC, including sedation, hypothermia,intestinal immobility, antinociception, analgesia, catalepsy,anti-emesis, and appetite stimulation.

Excessive exposure to Δ⁹-THC can lead to overeating, psychosis,hypotherimia, memory loss, and sedation. Specific synthetic ligands forthe cannabinoid receptors have been developed and have aided in thecharacterization of the cannabinoid receptors: CP55,940 (J. Pharmacol.Exp. Ther. 1988, 247, 1046-1051); WIN55212-2 (J. Pharmacol. Exp. Ther.1993, 264, 1352-1363); SR141716A (FEBS Lett. 1994, 350, 240-244; LifeSci. 1995, 56, 1941-1947); and SR144528 (J. Pharmacol. Exp. Ther. 1999,288, 582-589). The pharmacology and therapeutic potential forcannabinoid receptor ligands has been reviewed (Exp. Opin. Ther. Patents1998, 8, 301-313; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press,NY 1999, Vol. 34, 199-208; Exp. Opin. Ther. Patents 2000, 10, 1529-1538;Trends in Pharma. Sci. 2000, 21, 218-224). There is at least one CB₁modulator characterized as an inverse agonist or an antagonist,N-(1-piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide(SR141716A), in clinical trials for treatment of eating disorders.

Hitherto, several classes of CB₁ modulators are known. U.S. Pat. Nos.5,624,941 and 6,028,084, PCT Publication Nos. WO98/43636 and WO98/43635,and European Patent Application No. EP-658546 disclose substitutedpyrazoles having activity against the cannabinoid receptors. PCTPublication Nos. WO98/31227 and WO98/41519 also disclose substitutedpyrazoles having activity against the cannabinoid receptors. PCTPublication Nos. WO98/37061, WO00/10967, and WO00/10968 disclose diarylether sulfonamides having activity against the cannabinoid receptors.PCT Publication Nos. WO97/29079 and WO99/02499 disclosealkoxy-isoindolones and alkoxy-quinolones as having activity against thecannabinoid receptors. U.S. Pat. No. 5,532,237 disclosesN-benzoyl-indole derivatives having activity against the cannabinoidreceptors. U.S. Pat. No. 4,973,587, U.S. Pat. No. 5,013,837, U.S. Pat.No. 5,081,122, U.S. Pat. No. 5,112,820, and U.S. Pat. No. 5,292,736disclose aminoacylinidole derivatives as having activity against thecannabinoid receptors. PCT Publication No. WO03/027076 discloses1H-imidazole derivatives having CB₁ agonist, CB₁ partial agonist or CB₁antagonist activity. PCT Publication No. WO03/026648 discloses4,5-dihydro-1H-pyrazole derivatives having potent CB₁-antagonistactivity. US Publication No. US 2003/0114495 discloses substitutedimidazoles as cannabinoid receptor modulators. US Publication No. US2003/0119810 discloses pharmaceutical compositions containing3-aminoazelidine derivatives possessing a high affinity for CB₁receptors.

[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanoneRN 439128-75-3,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanoneRN394228-83-2, and[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone RN394228-85-4 are found in the CA database.

There still remains a need for potent low molecular weight CB₁modulators that have pharmacokinetic and pharmacodynamic propertiessuitable for use as human pharmaceuticals.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of formula I

wherein:

is a 6,5-bicyclic ring selected from the group consisting of:

R¹ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) alkylcarbonyl optionally substituted with heterocyclyl,    -   (c) heterocyclylcarbonyl optionally substituted with alkyl or        acetyl,    -   (d) alkyl or haloalkyl,    -   (e) cycloalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino and        dialkylamino,    -   (f) heterocyclyl selected from the group consisting of:

-   -   (g) aryl optionally substituted with halo, alkyl, alkoxy, cyano,        amino, alkylamino, or dialkylamino, and    -   (h) heteroaryl selected from the group consisting of:

R² is hydrogen, alkyl, heterocyclyl or, together with R¹ and the carbonto which they are attached, forms a saturated ring substituent selectedfrom the group consisting of:

-   -   (a) cycloalkyl, and    -   (b) heterocyclyl selected from the group consisting of:        tetrahydrofuranyl, tetrahydropyranyl and piperidinyl optionally        N-substituted with alkyl, acetyl or aryl,

X is —NR¹³R³ or

R³ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) alkyl optionally substituted with one or two substituents        independently selected from the group consisting of hydroxy,        alkoxy, halogen, amino, alkylamino, and dialkylamino,    -   (c) cycloalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        hydroxy, alkoxy, halo, amino, alkylamino, and dialkylamino,    -   (d) heterocyclyl selected from the group consisting of:

-   -   (e) cycloalkylalkyl selected from the group consisting of:

-   -   (f) heterocyclylalkyl selected from the group consisting of:

-   -   (g) arylalkyl selected from the group consisting of:

-   -    and    -   (h) heteroarylalkyl selected from the group consisting of:

is a heterocyclic ring selected from the group consisting of:

R⁴ is hydrogen, phenyl, halophenyl, acyl, or alkoxycarbonyl;

R⁵ is hydrogen, hydroxy or alkoxy;

each of R⁶ and R⁷ is independently selected from hydrogen, halo, cyano,alkyl, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino,alkoxycarbonyl, dialkylaminocarbonyl, aryl, and aryloxy;

R⁸ is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-SO₂—O—,R^(b)—NH—CH₂—, arylalkyl, or R^(c) ₂N—CO—O—;

R⁹ is hydrogen, hydroxy, hydroxyalkyl, acyl, halo, dihalo, oxo, aryl,haloarylalkyl, pyridinyl, alkyl-SO₂—O—, R^(a)—NH—, R^(b)—NH—CH₂—,arylalkyl,

or R^(c) ₂N—CO—O—;

R¹⁰ is hydrogen, alkyl, alkoxycarbonyl, aryl or haloaryl;

R¹¹ is hydrogen, alkyl or aryl;

R¹² is hydrogen or aryl;

R¹³ is hydrogen or alkyl;

R¹⁴ is hydrogen, allyl, aryl or acyl;

R^(a) is hydrogen, alkoxycarbonyl or halophenyl;

R^(b) is hydrogen, alkoxy, phenyl, halophenyl, halophenylalkyl,halopyridinyl, pyrimidinyl, alkoxycarbonyl, diallylaminocarbonyl ordialkylaminothiocarbonyl; and

R^(c) is hydrogen or alkyl; and all salts, solvates, optical andgeometric isomers, and crystalline forms thereof with the proviso thatthe compound of formula (I) is other than[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone, and[4-(2,3-dihydro-indole-1 sulfonyl)-phenyl]-piperidin-1-yl-methanone.

In a preferred embodiment,

is a 6,5-bicyclic ring selected from the group consisting of:

R¹ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) alkylcarbonyl optionally substituted with heterocyclyl,    -   (c) heterocyclylcarbonyl optionally substituted with alkyl or        acetyl,    -   (d) methyl, propyl, t-butyl or trifluoromethyl,    -   (e) cycloalkyl optionally substituted with oxo, hydroxy,        methoxy, difluoro or methyl,    -   (f) heterocyclyl selected from the group consisting of:

-   -   (g) phenyl optionally substituted with halo, methyl, methoxy,        cyano or dimethylamino, and    -   (h) heteroaryl selected from the group consisting of:

R² is H, methyl, ethyl, or together with R¹ and the carbon to which theyare attached, forms a saturated ring substituent selected from the groupconsisting of:

-   -   (a) cycloalkyl, and    -   (b) heterocyclyl selected from the group consisting of:        tetrahydropyranyl and N-methylpiperidin-4-yl;

X is —NR¹³R³ or

R³ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) (C₁-C₂) alkyl optionally substituted with (C₁-C₂) alkoxy,    -   (c) (C₄-C₆) cycloalkyl optionally substituted with one or two        substitutes independently selected from hydroxy, methoxy, amino,        alkylamino, and dialkylamino,    -   (d) heterocyclyl selected from the group consisting of:

-   -   (e) cycloalkylalkyl selected from the group consisting of:

-   -   (f) heterocyclylalkyl selected from the group consisting of:

-   -   (g) arylalkyl which is

-   -    and    -   (h) heteroarylalkyl selected from the group consisting of:

is a heterocyclic ring selected from the group consisting of:

R⁴ is hydrogen, phenyl, fluorophenyl, t-butyloxycarbonyl ormethoxycarbonyl;

R⁵ is hydrogen, hydroxy or methoxy;

each of R⁶ and R⁷ is independently selected from the group consisting ofhydrogen, alkyl, fluoro, chloro, trifluoromethyl, cyano, methoxy, amino,monomethylamino, dimethylamino, methoxycarbonyl anddimethylaminocarbonyl;

R⁸ is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-SO₂—O—,R^(b)—NH—CH₂—, arylalkyl or (CH₃)₂N—CO—O—;

R⁹ is hydrogen, hydroxy, hydroxymethyl, acetyl, fluoro, difluoro, oxo,phenyl, benzyl, pyridinyl, CH₃—SO₂—O—, R^(a)—NH—, R^(b)—NH—CH₂—,

or (CH₃)₂N—CO—O—;

R¹⁰ is hydrogen or alkyl;

R¹¹ is hydrogen or alkyl;

R¹² is hydrogen or phenyl;

R¹³ is hydrogen or methyl;

R¹⁴ is hydrogen, methyl, phenyl, or acetyl;

R^(a) is hydrogen, methoxycarbonyl, t-butyloxycarbonyl, or fluorophenyl;and

R^(b) is hydrogen, methoxy, phenyl, phenylalkyl, fluorophenylalkyl,fluorophenyl, pyridinyl, fluoropyridinyl, pyrimidinyl, methoxycarbonyl,t-butyloxycarbonyl, dimethylaminocarbonyl or dimethylaminothiocarbonyl.

In another preferred embodiment,

is selected from the group consisting of:

In another preferred embodiment,

In another preferred embodiment,

In another preferred embodiment, R¹ is aryl optionally substituted withhalo, alkyl, alkoxy, cyano, amino, alkylamino or dialkylamino. Morepreferably, R¹ is phenyl.

In another preferred embodiment, R¹ is cycloalkyl optionally substitutedwith one or two substituents independently selected from the groupconsisting of alkyl, halo, oxo, hydroxy alkoxy, amino, alkylamino anddialkylamino. More preferably, R¹ is cyclopentyl.

In another preferred embodiment, R¹ is heterocyclyl selected from thegroup consisting of:

More preferably, R¹ is tetrahydropyran-4-yl.

In another preferred embodiment, R³ is heterocyclylalkyl selected fromthe group consisting of:

More preferably, R³ is

In another preferred embodiment, R³ is heterocyclyl selected from thegroup consisting of:

More preferably, R³ is

In another preferred embodiment, R³ is cycloalkylalkyl selected from thegroup consisting of:

More preferably, R³ is

In another preferred embodiment, R³ is alkyl optionally substituted withone or two substituents independently selected from the group consistingof hydroxy, alkoxy, halogen, amino, alkylamino, and dialkylamino. Morepreferably, R³ is

In another preferred embodiment, R³ is arylalkyl selected from the groupconsisting of:

More preferably, R³ is

In another preferred embodiment, R³ is heteroarylalkyl selected from thegroup consisting of:

More preferably, R³ is

In another preferred embodiment, the present invention provides for acompound of formula I

wherein:

is a 6,5-bicyclic ring selected from the group consisting of:

R¹ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) alkylcarbonyl optionally substituted with heterocyclyl,    -   (c) heterocyclylcarbonyl optionally substituted with alkyl or        acetyl,    -   (d) alkyl or haloalkyl,    -   (e) cycloalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino and        dialkylamino,    -   (f) heterocyclyl selected from the group consisting of:

-   -   (g) aryl optionally substituted with halo, alkyl, alkoxy, cyano,        amino, alkylamino or dialkylamino, and    -   (h) heteroaryl selected from the group consisting of:

R² is hydrogen, alkyl, heterocyclyl or, together with R¹ and the carbonto which they are attached, forms a saturated ring substituent selectedfrom the group consisting of:

-   -   (a) cycloalkyl, and    -   (b) heterocyclyl selected from the group consisting of:        tetrahydrofuranyl, tetrahydropyranyl and piperidinyl optionally        N-substituted with alkyl, acetyl or aryl,

X is —NR¹³R³ or

R³ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) alkyl optionally substituted with one or two substituents        independently selected from the group consisting of hydroxy,        alkoxy, halogen, amino, alkylamino and dialkylamino,    -   (c) cycloalkyl optionally substituted with one or two        substituents independently selected from the group consisting of        hydroxy, alkoxy, halo, amino, alkylamino and dialkylamino,    -   (d) heterocyclyl selected from the group consisting of:

-   -   (e) cycloalkylalkyl selected from the group consisting of:

-   -   (f) heterocyclylalkyl selected from the group consisting of:

-   -   (g) arylalkyl selected from the group consisting of

-   -   (h) heteroarylalkyl selected from the group consisting of:

is a heterocyclic ring selected from the group consisting of:

R⁴ is hydrogen, phenyl, halophenyl, acyl or alkoxycarbonyl;

R⁵ is hydrogen, hydroxy or alkoxy;

each of R⁶ and R⁷ is independently selected from hydrogen, halo, cyano,alkyl, alkoxy, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino,alkoxycarbonyl, dialkylaminocarbonyl, aryl and aryloxy;

R⁸ is hydrogen, hydroxyalkyl, acyl, oxo, aryl, pyridinyl, alkyl-SO₂—O—,R^(b)—NH—CH₂—, arylalkyl, or R^(c) ₂N—CO—O—;

R⁹ is hydrogen, hydroxy, hydroxyalkyl, acyl, halo, dihalo, oxo, aryl,haloaryl-CH₂—, pyridinyl, alkyl-SO₂—O—, R^(a)—NH—, R^(b)—NH—CH₂—,arylalkyl,

or R^(c) ₂N—CO—O—;

R¹⁰ is hydrogen, alkyl, alkoxycarbonyl, aryl or haloaryl;

R¹¹ is hydrogen, alkyl or aryl;

R¹² is hydrogen or aryl;

R¹³ is hydrogen or allyl;

R¹⁴ is hydrogen, alkyl, aryl or acyl;

R^(a) is hydrogen, alkoxycarbonyl or halophenyl;

R^(b) is hydrogen, alkoxy, phenyl, halophenyl, halophenylalkyl,halopyridinyl, pyrimidinyl, alkoxycarbonyl, dialkylaminocarbonyl, ordialkylaminothiocarbonyl; and

R^(c) is hydrogen or alkyl;

and all optical and geometric isomers, and crystalline forms thereof andwith the proviso that the compound of formula (I) is other than[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone, and[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula I in an amount effectiveto antagonize CB-1 receptor stimulation, and a pharmaceuticallyacceptable carrier, diluent or excipient.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone, or[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone inan amount effective to antagonize CB-1 receptor stimulation, and apharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone, or[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanonein an amount effective to reduce endocannabinoid neurotransmissionthrough CB-1 receptors, and a pharmaceutically acceptable carrier,diluent or excipient.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone, or[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneand a pharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the present invention provides a method for treatinga condition which is treatable by reducing CB-1 receptor stimulation,comprising administering to a mammal in need thereof a compound ofFormula I or a pharmaceutical composition comprising a compound ofFormula I in an amount effective to antagonize CB-1 receptorstimulation, or to reduce endocannabinoid neurotransmission and apharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the present invention provides a method for treatinga condition which is treatable by reducing CB-1 receptor stimulation,comprising administering to a mammal in need thereof a compound selectedfrom the group consisting of a compound of Formula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone, and[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

In another aspect, the present invention provides a method for treatinga condition which is treatable by reducing CB-1 receptor stimulation,comprising administering to a mammal in need thereof a pharmaceuticalcomposition comprising a compound selected from the group consisting ofa compound of Formula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone, and[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanonein an amount effective to antagonize CB-1 receptor stimulation, or toreduce endocannabinoid neurotransmission and a pharmaceuticallyacceptable carrier, diluent or excipient.

In another aspect, the present invention provides for a compound ofFormula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone, or[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanonefor use in therapy.

In another aspect, the present invention provides use of a compound ofFormula I for the manufacture of a medicament for treating a conditionwhich is treatable by reducing CB-1 receptor stimulation.

In another aspect, the present invention provides use of a compound ofFormula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone, or[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanonefor the manufacture of a medicament for treating a condition which istreatable by reducing CB-1 receptor stimulation.

In another aspect, the present invention provides a method for treatinga condition selected from the group consisting of psychosis, memorydeficit, cognitive disorder, migraine, neuropathy, neuroinflammatorydisorder, cerebral vascular accident, head trauma, anxiety disorder,stress, depression, epilepsy, Parkinson's disease, schizophrenia,substance abuse disorder, obesity, and an eating disorder associatedwith excessive food intake comprising administering to the mammal inneed thereof a compound of Formula I,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-(4-phenyl-piperazin-1-yl)-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-morpholin-4-yl-methanone,[4-(2,3-dihydro-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone, or[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone.More preferably, the condition is obesity.

In a preferred embodiment, the condition which is treatable by reducingCB-1 receptor stimulation is psychosis, memory deficit, cognitivedisorder, migraine, neuropathy, neuroinflammatory disorder, cerebralvascular accident, head trauma, anxiety disorder, stress, depression,epilepsy, Parkinson's disease, schizophrenia, substance abuse disorder,obesity, or eating disorder associated with excessive food intake. Morepreferably, the condition is obesity.

In another preferred embodiment, the mammal being treated is a human. Inanother aspect, the invention provides for compounds of formula (IIa)

wherein:

Y is halogen, cyclopent-1-enyl, or cyclopentyl and R¹⁷ is alkyl.

It will be appreciated the all combinations of the aspects andembodiments discussed above and the examples discussed below arecontemplated as being encompassed by the present invention. In addition,all examples described herein are for illustrative purposes, and are notintended to narrow the scope of the invention in any way.

DETAILED DESCRIPTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

“Acyl” means an alkylcarbonyl (i.e., alkyl-CO—, wherein the alkyl groupis as herein described) or heterocyclylcarbonyl (i.e., heterocycyl-CO—,wherein heterocyclyl is as herein described). Preferred acyls contain alower alkyl (e.g., acetyl).

“Alkoxy” means an alkyl-O— group, wherein the alkyl group is as hereindescribed. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy,I-propoxy, and n-butoxy.

“Alkoxycarbonyl” means an alkyl-O—CO— group, wherein the alkyl group isas herein defined. Exemplary alkoxycarbonyl groups includemethoxycarbonyl, ethoxycarbonyl, or t-butyloxycarbonyl.

“Alkyl” means a saturated aliphatic hydrocarbon group, which may bestraight or branched, having 1 to 6 carbon atoms in the chain. Preferredalkyl groups have 1 to 4 carbon atoms in the chain. For example, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

“Alkylamino” means an alkyl-NH— group wherein the alkyl group is asherein described.

“Alkylcarbonyl” means alkyl-CO— group wherein the alkyl group is asherein described.

“Alkylthio” means an alkyl-S— group wherein the alkyl group is as hereindescribed. Exemplary alkylthio groups include methylthio, ethylthio,I-propylthio and n-butylthiothio.

“Aryl” means an aromatic mono- or bi-cyclic ring system of 6 to about 10carbon atoms. Exemplary aryl groups include phenyl and 1- and2-naphthyl.

“Arylalkyl” means an aryl-alkyl- group wherein the aryl and alkyl groupsare as defined herein.

“Aryloxy” means an aryl-O— group wherein the aryl group is as definedherein. Exemplary groups include phenoxy and naphthyloxy.

“Aryloxycarbonyl” means an aryl-O—C(O)— group wherein the aryl group isas defined herein. Exemplary aryloxycarbonyl groups includephenoxycarbonyl and naphthoxycarbonyl.

“Arylthio” means an aryl-S— group wherein the aryl group is as hereindescribed. Exemplary arylthio groups include phenylthio andnaphthylthio.

“Carboxy” means a HO(O)C— (i.e., carboxylic acid) group.

“Cycloalkyl” means a fully saturated, mono-carbocyclic ring system ofabout 3 to about 6 carbon atoms. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Cycloalkylalkyl” means cycloalkyl-alkyl- group wherein the cycloalkylgroup and the alkyl group are as defined herein.

“Dialkylamino” means an (alkyl)₂-N— group wherein the alkyl group is asdefined herein. It is understood that the two alkyl groups can be thesame or different.

“Dialkylaminocarbonyl” means a (alkyl)₂-N—C(O)— group wherein the alkylgroup is as defined herein. It is understood that the two alkyl groupscan be the same or different.

“Dialkylaminothiocarbonyl” means a dialkylamino-C(S)— group wherein thedialkylamino group is as defined herein. It is understood that the twoalkyl groups can be the same or different.

“Effective amount” is means an amount of a compound/compositionaccording to the present invention effective in producing the desiredtherapeutic effect.

“Halo” means fluoro, chloro, bromo, or iodo. A preferred halo is fluoro.

“Haloalkyl” refers to an alkyl group, as described herein, which issubstituted with one to six halo groups, as described herein. Preferredhaloalkyls include fluoroalkyls, such as fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,1,1,2,2,2-pentafluoroethyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, and1,1,1,3,3,3-hexafluoroprop-2-yl.

“Haloalkoxy” refers to an alkoxy group, as described herein, which issubstituted with one to six halo groups, as described herein. Preferredhaloalkoxy groups include fluoroalkoyls, such as fluoromethoxy,difluoromethoxy, trifluoromethoxy.

“Haloaryl” refers to an aryl group, as described herein, which issubstituted by halogen, as described herein.

“Haloarylalkyl” refers to an allyl group, as described herein, which issubstituted by a haloaryl group, as described herein.

“Halophenyl” refers to a phenyl group which is substituted by halogen,as described herein.

“Halophenylalkyl” refers to an alkyl group, as described herein, whichis substituted by a halophenyl group, as described herein.

“Halopyridinyl” refers to a pyridinyl group which is substituted by ahalogen group, as described herein.

“Heteroaroyl” means a heteroaryl-CO— group, wherein the heteroaryl groupis as herein described. Exemplary groups include thiophenoyl,nicotinoyl, pyrrol-2-ylcarbonyl, 1- and 2-naphthoyl, and pyridinoyl.

“Heteroaryl” means a monocyclic or bicyclic fully unsaturated ringsystem of about 5 to 10 ring atoms in which one or two of the ring atomsis a hetero element(s) other than carbon (e.g., nitrogen, oxygen orsulfur) and the remainder of the ring atoms are carbon. Preferred ringsizes include 5 to 6 ring atoms. Exemplary heteroaryl groups includepyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, and isoquinolinyl.

“Heteroarylalkyl” means heteroaryl-alkyl- wherein the heteroaryl groupis as described herein.

“Heterocyclyl” means a monocyclic, fully-saturated ring system of about3 to about 7 ring atoms, in which one or two of the ring atoms is ahetero element(s) other than carbon (e.g., nitrogen, oxygen or sulfur)and the remainder of the ring atoms are carbon. Heterocyclyl groups maybe optionally substituted, for example with alkyl, hydroxy, alkoxy,aryl, acyl, in particular, methyl, phenyl, halophenyl, alkoxycarbonyl.Exemplary heterocyclyl rings, for example include pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, piperidyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperazinyl, morpholinyl, and thiomorpholinyl.

“Heterocyclyalkyl” means heterocycly-alkyl- wherein the heterocyclylgroup is as herein described.

“Hydrate” means a solvate, as defined herein, wherein the solventmolecule(s) is/are H₂O.

“Hydroxyalkyl” means HO-alkyl- group, wherein the alkyl group is asherein described.

“Obesity” refers to a condition whereby a mammal has a Body Mass Index(BMI), which is calculated as weight per height squared (kg/m²), of atleast 25.9. Conventionally, those persons with normal weight have a BMIof 19.9 to less than 25.9.

“Phenylalkyl” refers to an alkyl group, as described herein, which issubstituted by a phenyl group.

The term “salt(s)” refers to pharmaceutically acceptable salts, asdefined herein.

“Pharmaceutically acceptable salts” refers to the relatively non-toxic,inorganic and organic acid addition salts, and base addition salts, ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds. Inparticular, acid addition salts can be prepared by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Exemplary acidaddition salts include the hydrobromide, hydrochloride, sulfate,bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,palmitate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate,mesylate, glucoheptonate, lactiobionate, sulphamates, malonates,salicylates, propionates, methylene-bis-β-hydroxynaphthoates,gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates,ethanesulphonates, benzenesulphonates, p-toluenesulphonates,cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like.See, for example S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm.Sci., 66, 1-19 (1977) which is incorporated herein by reference. Baseaddition salts can also be prepared by separately reacting the purifiedcompound in its acid form with a suitable organic or inorganic base andisolating the salt thus formed. Base addition salts includepharmaceutically acceptable metal and amine salts. Suitable metal saltsinclude the sodium, potassium, calcium, barium, zinc, magnesium, andaluminum salts. The sodium and potassium salts are preferred. Suitableinorganic base addition salts are prepared from metal bases whichinclude sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide,zinc hydroxide. Suitable amine base addition salts are prepared fromamines which have sufficient basicity to form a stable salt, andpreferably include those amines which are frequently used in medicinalchemistry because of their low toxicity and acceptability for medicaluse for example, ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, e.g., lysine andarginine, and dicyclohexylamine, and the like.

“Prevention” (of obesity) refers to preventing obesity from occurring ifthe treatment is administered prior to the onset of the obese condition.Moreover, if treatment is commenced in already obese subjects, suchtreatment is expected to prevent, or to prevent the progression of, themedical sequelae of obesity, such as, e.g., arteriosclerosis, Type IIdiabetes, polycystic ovarian disease, cardiovascular diseases,osteoarthritis, dermatological disorders, hypertension, insulinresistance, hypercholesterolemia, hypertriglyceridemia, andcholelithiasis.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association includeshydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvate”encompasses both solution-phase and isolable solvates. Exemplarysolvates include hydrates, ethanolates, methanolates, and the like.

“Substance abuse disorders” includes substance dependence or abuse withor without physiological dependence. The substances associated withthese disorders are: alcohol, amphetamines (or amphetamine-likesubstances), caffeine, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine (or phencyclidine-like compounds),sedative-hypnotics or benzodiazepines, and other (or unknown) substancesand combinations of all of the above. In particular, the term “substanceabuse disorders” includes drug withdrawal disorders such as alcoholwithdrawal with or without perceptual disturbances; alcohol withdrawaldelirium; amphetamine withdrawal; cocaine withdrawal; nicotinewithdrawal; opioid withdrawal; sedative, hypnotic or anxiolyticwithdrawal with or without perceptual disturbances; sedative, hypnoticor anxiolytic withdrawal delirium; and withdrawal symptoms due to othersubstances. It will be appreciated that reference to treatment ofnicotine withdrawal includes the treatment of symptoms associated withsmoking cessation. Other “substance abuse disorders” includesubstance-induced anxiety disorder with onset during withdrawal;substance-induced mood disorder with onset during withdrawal; andsubstance-induced sleep disorder with onset during withdrawal.

“Therapeutically effective amount” means the amount the compound ofstructural formula I that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician.

“Treatment” or “treating” (of obesity) refers to reducing the BMI of themammal and in certain cases where it is desirable for weight loss. Thetreatment or treating suitably results in a reduction in food or calorieintake by the mammal.

The symbol “

” or “{tilde over ( )}” in a molecular structure indicates the positionof attachment for that particular substituent.

When any variable (e.g., R¹, R^(d), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. In choosing compounds ofthe present invention, one of ordinary skill in the art will recognizethat the various substituents, i.e. R¹, R², etc., are to be chosen inconformity with well-known principles of chemical structureconnectivity.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, an arylcarbonylaminoalkyl substituent is equivalent toaryl-C(O)—NH-alkyl-.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. Such an example maybe a ketone and its enol form known as keto-enol tautomers. Theindividual tautomers as well as mixture thereof are encompassed withcompounds of Formula I.

Compounds of the Formula I may be separated into diastereoisomeric pairsof enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or ethyl acetate or a mixturethereof. The pair of enantiomers thus obtained may be separated intoindividual stereoisomers by conventional means, for example by the useof an optically active amine as a resolving agent or on a chiral HPLCcolumn.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

The present invention also provides novel crystalline forms of thecompounds of formula (I). Novel crystalline forms may be prepared bycrystallization under controlled conditions. Crystallization from asolution and slurrying techniques are contemplated to be within thescope of the present process. In practice, a number of factors caninfluence the form obtained, including temperature, solvent compositionand also optional seeding. Seed crystals can be obtained from previoussynthesis of the compound in which crystals were isolated.

A number of methods are available to characterize crystalline forms oforganic compounds. For example, methods include differential scanningcalorimetry, solid state NMR spectrometry, infra-red spectroscopy, andX-ray powder diffraction. Among these X-ray powder diffraction and solidstate NMR spectroscopy are very useful for identifying anddistinguishing between crystalline forms.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Compounds of this invention are modulators of the CB1 receptor and assuch are useful for the prevention and treatment of disorders ordiseases associated with the CB1 receptor. Accordingly, another aspectof the present invention provides a method for the treatment (includingprevention, alleviation, amelioration or suppression) of diseases ordisorders or symptoms mediated by CB1 receptor binding and subsequentcell activation, which comprises administering to a mammal an effectiveamount of a compound of Formula I. Such diseases, disorders, conditionsor symptoms are, for example, but not limited to, psychosis, memorydeficits, cognitive disorders, migraine, neuropathy, anxiety disorders,depression, stress, epilepsy, Parkinson's disease, schizophrenia,substance use disorders, particularly to opiates, alcohol, and nicotine,obesity, and eating disorders associated with excessive food intake. SeeDSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders.Revised, 4^(th) Ed., Text Revision (2000). See also DSM-IV, Diagnosticand Statistical Manual of Mental Disorders 4^(th) Ed., (1994). TheDSM-IV and DSM-IV-TR were prepared by the Task Force on Nomenclature andStatistics of the American Psychiatric Association, and providesdescriptions of diagnostic categories. The skilled artisan willrecognize that there are alternative nomenclatures, nosologies, andclassification systems for pathologic psychological conditions and thatthese systems evolve with medical scientific progress.

The obesity herein may be due to any cause, whether genetic orenvironmental. Examples of disorders that may result in obesity or bethe cause of obesity include overeating and bulimia, polycystic ovariandisease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich'ssyndrome, Type II diabetes, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. In addition, the compound of formula (I) can beused to ameliorate weight gain, whether or not the associated weightgain can be classified as clinically obese.

The method of treatment of this invention comprises a method ofmodulating the CB1 receptor and treating CB1 receptor mediated diseasesby administering to a patient in need of such treatment a non-toxictherapeutically effective amount of a compound of this invention thatselectively antagonizes the CB1 receptor in preference to the other CBor G-protein coupled receptors.

“Neutral antagonists” are ligands without intrinsic activity, i.e. theydo not influence the receptor's own activity (constitutive receptoractivity) and prevent competitively the binding of an agonist (oftenendogenous) to the receptor.

“Inverse agonists” are ligands with negative intrinsic activity, theyinhibit the receptor's own activity (constitutive receptor activity)shifting the equilibrium of the receptor conformation to its inactivestate.

There is evidence suggesting that CB1 receptor ligands act as eitherneutral antagonists or inverse agonists; these ligands will reduceendocannabinoid neurotransmission through CB1 receptors either bycompetitive receptor antagonism or by receptor inactivation,respectively.

Compounds of formula Ia (i.e., compounds of Formula I wherein

can be prepared according to the processes illustrated in Scheme 1.

In Scheme 1, Step a involves the introduction of R¹-substitution at the3-position on the indole moiety of compound (1), (IIa) or (IIc) (whereinY is I, Br, B(OH)₂,

or SnMe₃) under standard conditions employed for palladium mediatedcross-coupling reactions. For example, a 3-haloindole of formula (1),(IIa), or (IIc) is reacted with a suitable aryl boronic acid(Suzuki-type) or with a suitable aryl stannane (Stille-type), asgenerally described in Handbook of Palladium Catalyzed OrganicReactions, Malleron. J.-L.; Fiaud, J.-C.; Legros, J.-Y.; Academic Press,USA, 1997, p. 23-47. It is understood by one of ordinary skill in theart that, in general, an aryl boronic ester can be used in place of thearyl boronic acid in the palladium cross-coupling reactions describedherein. By way of illustration, the aryl boronic acids include, but arenot limited to, the following:

More specifically, compound (1), (IIa) or (IIc) (Y is I or Br) and thesuitable aryl boronic acid or the suitable aryl boronic ester, alongwith a base (e.g., aqueous sodium carbonate) and a catalyst (e.g.,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex) aredissolved in a suitable solvent such as dichloromethane, and the mixtureis heated. Aqueous work-up and chromatographic purification affords thedesired compound (2), (IIb) or (Ia). More specifically, in theStille-type reaction, a 3-iodoindole compound (1), (IIa) or (IIc) iscombined with an aryl stannane (e.g., 2-tributylstannyl pyrazine,3-tributylstannylpyridine, 2-tributylstannylpyridine) and a catalyst(e.g., tetrakis(triphenylphosphine)Pd(0)) in an appropriate solvent(e.g., DMF) and heated. After an aqueous work-up, compound (2), (Ia) or(IIb) is isolated by chromatographic purification.

Alternatively, a 3-haloindole compound (1), (IIa) or (IIc) is subjectedto a palladium-mediated coupling with an olefin (e.g., cyclopentene) oran α,β-unsaturated ketone or ester (Heck-type), then the resultingintermediate is hydrogenated to provide the desired compound (2), (IIb)or (Ia). (see generally Handbook of Palladium Catalyzed OrganicReactions, Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y.; Academic Press,USA 1997 p. 61-71.) More specifically, a 3-iodoindole compound (1),(IIa) or (IIc) is combined with an olefin and a catalyst (e.g.,palladium (II) acetate) along with tetrabutylammonium chloride and abase (e.g., potassium acetate) and the resulting mixture heated. Afteran aqueous work-up, the intermediate product is isolated bychromatographic purification, then subjected to hydrogenation to removethe resulting olefin, thereby providing the desired compound (2), (Ia),or (IIb).

Alternatively, a 3-haloindole compound (1), (IIa) or (IIc) is subjectedto a metal halogen exchange with a reagent such as cyclopentyl magnesiumbromide and then treated with a ketone such astetrahydro-4H-pyran-4-one. The resulting alcohol is isolated and treatedwith a reducing agent (e.g., triethylsilane and TFA) to provide thedesired compound (2), (Ia) or (IIb).

Alternatively, a compound (1), (IIa), or (IIc) when Y is B(OH)₂,

or SnMe₃ is reacted via a palladium-mediated coupling employing asuitable aryl halide in a manner analogous procedure set forth above. Byway of illustration, suitable aryl halides include, but are not limitedto, 5-bromo-2-methoxy pyridine, 5-bromo-2-fluoro-pyridine,2-bromo-5-chloro-thiophene, 4-bromo-isoquinoline,2-bromo-5-chloro-thiophene, 3-bromo-toluene, 4-bromo-toluene,1-bromo-3-methoxy-phenyl, 6-bromo-quinoline,1-bromo-4-dimethylamino-phenyl, 1-bromo-3-fluoro-pyridine,2-bromo-pyrimidine and 5-bromo-pyrimidine.

In scheme 1 step b, a sulfonamide of formula (Ia), (IIa), (IIb) or (IIc)is prepared via treatment of the appropriate indole of formula (1) or(2) with the requisite sulfonyl chloride of formula (3) or (4) in thepresence of a base under standard conditions. More specifically, theindole of formula (1) or (2) and the sulfonyl chloride of formula (3) or(4) are combined with a base (e.g., diisopropylethylamine, potassiumtertbutoxide or sodium hydride) in an appropriate solvent (e.g.,N,N-dimethylformamide, dioxane or tetrahydrofuran). Alternatively, theindole of formula (1) or (2) and sulfonyl chloride of formula (3) or (4)are combined with a catalyst (e.g., DMAP or 4-pyrrolidin-1-yl-pyridine)with or without a base in an appropriate solvent (e.g.,N,N-dimethylformamide, dioxane or acetonitrile). An aqueous work-up andchromatographic purification affords compound (Ia), (IIa), (IIb) or(IIc).

In Scheme 1, step c, the conversion of an ester of formula (IIb) to anamide of formula (Ia) is achieved under standard conditions via thecarboxylic acid or acid chloride, as referenced in Comprehensive OrganicTransformations, R. C. Larock VCH Publishers Inc, New York, N.Y. 1989.p. 972-976. More Specifically, the ester of formula (IIb) is hydrolyzedto the acid in the presence of a base (e.g., sodium hydroxide),converted to the acid chloride with reagents such as oxalyl chloride,and then treated with the requisite amine in the presence of a base(e.g., triethylamine) to form the compound (Ia). Alternatively the acidis coupled with the amine using a coupling reagent (e.g., EDC, BOP orPyBOP) with or without a catalyst (e.g., NHS). After an aqueous work-up,the products are isolated by chromatographic purification to yield thecompound (Ia).

Compounds of formula (Ia) can also be prepared according to theprocesses illustrated in Scheme 2.

In Scheme 2, step a, direct alkylation of a compound (5), (IId) or (IIe)is achieved via heating with a ketone (e.g., cyclohexanone or2-methoxycyclohexanone) and a base (e.g., potassium hydroxide). Theresulting olefin is hydrogenated to form a compound of formula (2),(IIb), or (Ia) (see, e.g., J. Med. Chem. (1997), 40, 250).Alternatively, direct alkylation of a compound of formula (5), (IId),(IIe) is achieved under protic or lewis acid conditions with an alcohol(e.g., tert-butyl alcohol) or alkyl bromide (e.g., as described in J.Org. Chem. (2002), 67, 2705). Alternatively, conjugate addition to anα,β-unsaturated ketone is achieved in the presence of indium tribromideand isopropylamine in solvents such as dichloromethane, as described inJ. Org. Chem (2002), 67, 3700 to form compound (2), (IIb), or (Ia).Steps b and c in Scheme 2 are carried out as described in steps b and cof Scheme 1, respectively.

It should be noted that when R¹ is

step a of Schemes 1 and 2 must be modified as shown in Scheme 3.

In Scheme 3, step a1, a 3-amino □eaction□ed indole compound (2a) isprepared via a palladium-mediated coupling of an amine with a3-haloindole of formula (6) bearing a protecting group on nitrogen (asdescribed for example in Organic Lett. (2002), 4, 2885) followed byremoval of the N-protecting group. More specifically, 3-bromoindoleN-protected with a triisopropylsilanyl group is combined with an amine(e.g., piperidine, morphline, or 1-methyl piperazine), a catalyst (e.g.,tris(dibenzylideneacetone)dipalladium(0) chloroform adduct and2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl), and a base(e.g., lithium bis(trimethylsilyl)amide), and the mixture heated in anappropriate solvent (e.g., THF). The resulting intermediate isdeprotected with tetrabutyl ammonium fluoride, after which an aqueouswork-up and chromatographic purification yields isolated compound (2a).

Compounds of formula Ib (i.e. where

is

can be synthesized by methods known in the art, as illustrated in Scheme4.

In Scheme 4, step a involves reduction of the indole compound (2) to thecorresponding indoline compound (7) utilizing standard conditions suchas sodium borohydride or sodium cyanoborohydride, and as described inYamamoto, Y et al. Bull Chem. Soc. Jpn 44, 1971, 541-545. Step binvolves reaction of the indoline compound (7) with the appropriatesulfonyl chloride compound (4) or (3) under standard conditionsdescribed above in Scheme 1 or 2. Alternatively, the indole compound (2)is coupled to the sulfonyl chloride according to Schemes 1, 2, or 3,followed by reduction according to step a to give (Ib). Alternatively,compound (Ia) can be prepared by one of the general methods found inSchemes 1, 2 or 3. In general, when R¹ is aryl, step a is accomplishedas the first step. When R¹ is alkyl or cycloalkyl, step b isaccomplished as the first step. Compounds, wherein R¹ and R² are takentogether to form a ring as synthesized by methods known in the art.

The examples set forth herein represent typical syntheses of thecompounds of the present invention. The reagents and starting materialsare readily available to one of ordinary skill in the art.

Preparation 1 3-(6-Methoxy-cyclohex-1-enyl)-1H-indole

Add 5 ml dry MeOH to a flask under N₂ containing indole (1 g, 8.5 mmol,8.5 eq) and potassium hydroxide (202 mg, 3.59 mmol, 1 eq). Add to thissolution 2-Methoxy-cyclohexanone (834 mg, 6.5 mmol, 6.5 eq). Heatreaction to 63° C. for 18 hours. Cool reaction and purify crude materialby silica gel chromatography to give 442 mg (30% yield) of3-(6-Methoxy-cyclohex-1-enyl)-1H-indole as a waxy yellow solid. MassSpectrum (m/e): 228.02 (MH+).

Preparation 2 3-(2-Methoxy-cyclohexyl)-1H-indole

Treat 3-(6-methoxy-cyclohex-1-enyl)-1H-indole (200 mg, 0.879 mmol) with10% Pd/C (40 mg) in EtOAc under atmospheric hydrogenation conditions for1.5 hours. Filter resulting solution over Celite to remove catalyst.Concentrate crude on rotovap and purify on silica gel chromatography togive 3-(2-Methoxy-cyclohexyl)-1H-indole (127 mg, 63% yield). MassSpectrum (m/e): 230.03 (MH+), 228.14 (M−).

Preparation 3 3-(1H-Indol-3-yl)-cyclopentanone

Conduct reaction according to literature procedure (JOC, vol 67, 2002,pg 3700-3704) to give final 3-(1H-Indol-3-yl)-cyclopentanone (1.38 g,81% yield) as a light pink solid. Mass Spectrum (m/e): 199.99 (MH+).

Preparation 10 N-[2-Phenyl-eth-(Z)-ylidene]-N′-pyridin-4-yl-hydrazine

React 4-hydrazinopyridine HCl with phenylacetaldehyde under literatureconditions (J Chem Soc, 1959, pg 3830). Instead of NH₃, neutralize with1N NaOH and extract with CHCl₃. Dry organics over MgSO₄ and concentrateon rotovap to giveN-[2-Phenyl-eth-(Z)-ylidene]-N′-pyridin-4-yl-hydrazine (7.3 g, approxquantitative) as a crude thick oil that can be used without furtherpurification. Mass Spectrum (m/e): 212.02 (MH+).

Preparation 11 3-Phenyl-1H-pyrrolo[3,2-c]pyridine

React crude N-[2-Phenyl-eth-(Z)-ylidene]-N′-pyridin-4-yl-hydrazine (7.25g, 34.22 mmol) under literature conditions (Can J Chem, vol 44, 1966, pg2455) to give 3-Phenyl-1H-pyrrolo[3,2-c]pyridine (2.28 g, 34% yield)after silica gel chromatography: Mass Spectrum (m/e): 194.96 (MH+).

Preparation 12 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride

Add 4-chlorosulfonyl-benzoyl chloride (103 g (0.433 mol) and anhydrousTHF (1.2 L) to a 5-L 3-neck round bottom equipped with overhead stirrer,dropping funnel, N₂ line, and temperature probe and cool to −78° C. Addto the stirring solution dropwise over 4 h a solution of4-fluorobenzylamine (52 g, 0.416 mol), triethylamine (42 g, 0.415 mol),and 4-DMAP (5.3 g, 0.043 mol) in dry THF (1.2 L). Slowly bring to roomtemperature the resulting mixture and stir overnight. Filter the solids,back-wash with THF, and concentrate the filtrate to a solid. Partion thesolid between 1N HCl (1 L) and ethyl acetate (2×1 L). Combine theorganics, dry over magnesium sulfate, filter, and concentrate to asolid. Suspend the solid in methyl t-butyl ether (1 L), stir at roomtemperature for 2 h, filter, and back-wash with ethyl ether (500 mL).Dry the resulting white powder (20 mm Hg, 40° C.) to give4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride as a white solid(108.5 g, 80%): ¹HNMR (DMSO-d₆) δ 9.07 (t, J=5.9 Hz, 1H), 7.82 (d, J=8.3Hz, 2H), 7.65 (d, J=7.8 Hz, 2H), 7.35 (m, 2H), 7.14 (t, J=8.8 Hz, 2H),4.44 (d, J=5.9 Hz, 2H); MS (ESI) m/z 326 (m−H); HPLC, 93.6%.

Preparation 14 3-(3,3-Difluoro-cyclopentyl-1H-indole

Following a literature procedure (Tet, Vol 46, No 13-14, pg 4925, 1990)previously reported to convert 3-(1H-Indol-3-yl)-cyclopentanone to3-(3,3-difluoro-cyclopentyl)-1H-indole (246 mg, 22% yield): MassSpectrum (m/e): 220.11 (MH−).

Preparation 15 3-Morpholin-4-yl-1-triisopropylsilanyl-1H-indole

Combine 3-bromo-1-triisopropylsilanyl-1H-indole (0.33 g, 0.94 mmol),morpholine (0.10 mL, 1.15 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.012 g, 0.03mmol), and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct(0.012 g, 0.01 mmol) in a pressure tube. Add 1N solution of lithiumbis(trimethylsilyl)amide in THF (2.00 mL, 2.00 mmol), flush tube withnitrogen gas, and close the tube. Stir at 65° C. for 18 h, cool to roomtemperature, dilute with water, and extract with EtOAc. Wash EtOAc layerwith water, brine, dry (Na₂SO₄), and concentrate under vacuum. Purifythe residue by flash chromatography using 0 to 50% of EtOAc in hexanesto give the title compound (0.20 g 60%): MS (ES) 359.1 (M+1)+.

Preparation 163-(4-Methyl-piperazin-1-yl)-1-triisopropylsilanyl-1H-indole

Following a method similar to3-morpholin-4-yl-1-triisopropylsilanyl-1H-indole using3-bromo-1-triisopropylsilanyl-1H-indole (0.70 g, 1.99 mmol),1-methyl-piperazine (0.30 g, 3.00 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.02 g, 0.05mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.05g, 0.05 mmol) and 1N solution of lithium bis(trimethylsilyl)amide in THF(2.40 mL). Purify by flash chromatography using 0 to 12% of MeOH indichloromethane to give the title compound (0.23 g, 32%). MS (ES) 372.1(M+1)⁺.

Preparation 17 3-Piperidin-1-yl-1-triisopropylsilanyl-1H-indole

Following a method similar to3-morpholin-4-yl-1-triisopropylsilanyl-1H-indole using3-bromo-1-triisopropylsilanyl-1H-indole (0.70 g, 1.99 mmol), piperidine(0.26 g, 3.04 mmol),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.02 g, 0.05mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.05g, 0.05 mmol) and 1N solution of lithium bis(trimethylsilyl)amide in THF(2.40 mL) to prepare the title compound. Purify by flash chromatographyusing 0 to 40% of EtOAc in hexanes to give the title compound (0.20 g,29%): MS (ES) 357.1 (M+1)⁺.

Preparation 18 3-Morpholin-4-yl-1H-indole

Add 1N solution of tetrabutylammonium fluoride (0.70 mL, 0.70 mmol) to asolution of 3-Morpholin-4-yl-1-triisopropylsilanyl-1H-indole (0.20 g,0.56 mmol) in THF (2.0 mL). Stir at room temperature for 2 h, dilutewith water, and extract with EtOAc. Wash EtOAc with saturated NaHCO₃,water, dry (Na₂SO₄), and concentrate under vacuum. Purify the residue byflash chromatography using 20 to 80% of EtOAc in hexanes to give thetitle compound (0.10 g 89%). MS (ES) 203.1 (M+1)+.

Preparation 19 3-(4-Methyl-piperazin-1-yl)-1H-indole

Following a method similar to 3-morpholin-4-yl-1H-indole using3-(4-Methyl-piperazin-1-yl)-1-triisopropylsilanyl-1H-indole (0.35 g,0.94 mmol) and 1N solution of tetrabutylammonium fluoride (1.40 mL) toprepare the title compound. Purify by flash chromatography using 2 to12% methanol in dichloromethane to give the title compound (0.12 g 60%).MS (ES) 216.1 (M+1)+.

Preparation 20 3-Piperidin-1-yl-1H-indole

Following a method similar to 3-morpholin-4-yl-1H-indole using3-Piperidin-1-yl-1-triisopropylsilanyl-1H-indole (0.30 g, 0.84 mmol) and1N solution of tetrabutylammonium fluoride (1.30 mL). Purify by flashchromatography using 20 to 50% of EtOAc in hexanes to give the titlecompound (0.12 g 71%). MS (ES) 201.1 (M+1)+.

Preparation 21 1-(2-Fluoro-phenyl)-cyclobutanecarbonitrile

Slowly add NaH (922 mg, 23.0 mmol) to a solution of(2-fluorophenyl)-acetonitrile (1.27 mL, 9.95 mmol) in DMSO (40.0 mL).Stir the mixture at RT for 30 mins then add via cannula a solution of1,3-dichloropropane (0.95 mL, 10.0 mmol) in DMSO (20 mL). After additionis complete stir at 75° C. for 5 h. Pour mixture over ice (60 g) andextract with Et₂O (3×50 mL). Combine the organic solutions and wash withbrine (50 mL), dry filter and concentrate. Purify the material by flashchromatography (using a linear gradient of 100% hexanes to 35%EtOAc/hexanes) to give the title compound (1.4 g, 80%) as a yellow oil.¹H NMR (400 MHz, CDCl₃): δ 7.32 (m, 1H), 7.25 (dt, 1H, J=1.9, 8.0), 7.16(dt, 1H, J=0.9, 7.5), 7.09 (ddd, 1H, J=1.2, 8.1, 10.7), 2.86 (m, 2H),2.69 (m, 2H), 2.50 (m, 1H), 2.05 (m, 1H).

Preparation 22 4-(2-Fluoro-phenyl)-tetrahydro-pyran-4-carbonitrile

Slowly add NaH (920 mg, 23.0 mmol) to a solution of(2-fluorophenyl)-acetonitrile (1.27 mL, 9.95 mmol) in DMSO (40.0 mL).Stir the mixture at RT for 30 mins then add via cannula a solution of1,3-dichloropropane (1.0 mL, 8.53 mmol) in DMSO (20 mL). After additionis complete stir at 75° C. for 5 h. Pour mixture over ice (60 g) andextract with Et₂O (3×50 mL). Combine the organic solutions and wash withbrine (50 mL), then dry filter and concentrate. Purify the material byflash chromatography (using a linear gradient of 100% hexanes to 35%EtOAc/hexanes) to give the title compound (1.4 g, 80%) as a yellow oil.¹HNMR (400 MHz, CDCl₃): δ 7.43 (dt, 1H, J=1.7, 7.9), 7.36 (m, 1H), 7.19(dt, 1H, J=1.4, 7.7), 7.13 (ddd, 1H, J=1.4, 6.6, 14.5), 4.08 (m, 2H),3.94 (dt, 2H, J=1.7, 7.9), 2.26 (dt, 2H, J=4.4, 13.7), 2.19 (m, 2H).

Preparation 23

Spiro[indoline-3,4′-tetrahydro-pyran]

Add LiAlH₄ (398 mg, 10.5 mmol) to a solution of4-(2-fluoro-phenyl)-tetrahydro-pyran-4-carbonitrile (1.39 g, 6.77 mmol)in dimethoxyethane (25 mL). Stir the solution at reflux overnight thenadd aq. Satd Rochelle's salt solution (30 mL) and stir for an additional1 h at RT. Extract the mixture with CH₂Cl₂ (3×30 mL). Combine theorganic extracts and wash with additional aq satd Rochelle's saltsolution (30 mL) and brine (30 mL). Dry, filter and concentrate theorganic solution then purify the crude material by flash chromatography,using a linear gradient of 100% hexanes and 50% EtOAc/hexanes, to givethe title compound (581 mg, 45%) as a white solid. ¹H NMR (400 MHzCDCl3): δ 7.09 (d, 1H, J=7.3), 7.06 (t, 1H, J=7.6), 6.77 (m, 1H), 6.67(m, 1H), 3.97 (m, 2H), 3.94 (dt, 2H, J=1.7, 7.9), 3.56 (dt, 2H, J=2.1,11.8), 3.55 (s, 2H), 1.99 (m, 2H), 1.67 (m, 2H).

Preparation 24 C-[1-(2-Fluoro-phenyl)-cyclobutyl]-methylamine

Add LiAlH₄ (461 mg, 12.1 mmol) to a solution of1-(2-fluoro-phenyl)-cyclobutanecarbonitrile (1.38 g, 7.88 mmol) indimethoxyethane (30 mL). Stir the solution at reflux overnight then addaq. Satd Rochelle's salt solution (30 mL) and stir for an additional 1 hat RT. Extract the mixture with CH₂Cl₂ (3×30 mL). Combine the organicextracts and wash with additional aq satd Rochelle's salt solution (30mL) and brine (30 mL). Dry, filter and concentrate the organic solutionthen purify the crude material by flash chromatography, using 20%MeOH/CH₂Cl₂, to give the title compound (1 g, 71%) as a white solid. MS(ES) 180.1 (M+1)+.

Preparation 25 Spiro[cyclobutane-1,3′-indoline]

Add LiAlH₄ (266 mg, 7.01 mmol) to a solution of4-(2-fluoro-phenyl)-tetrahydro-pyran-4-carbonitrile (488 mg, 2.72 mmol)in dimethoxyethane (30 mL). Stir the solution at reflux for 4d, then addaq. Satd Rochelle's salt solution (30 mL) and stir for an additional 1 hat RT. Extract the mixture with Et₂O (3×30 mL). Combine the organicextracts and wash with brine (30 mL). Dry, filter and concentrate theorganic solution then purify the crude material by flash chromatography,using a linear gradient of 100% hexanes to 30% EtOAc/hexanes, to givethe title compound (44 mg, 10%) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 7.31 (m, 1H), 7.03 (dt, 1H, J=1.4, 7.5), 6.79 (dt, 1H, J=0.9,7.5), 6.64 (d, 1H, J=7.9), 2.36 (m, 2H), 2.21 (m, 2H), 2.02 (m, 2H).

Preparation 26 3-Cyclopropyl-1-triisopropylsilanyl-1H-indole

Dissolve 3-bromo-1-triisopropylsilanyl-1H-indole (1.02 g, 2.89 mmol),cyclopropylboronic acid (259 mg, 3.01 mmol) and K₃PO₄ (1.8 g, 8.5 mmol)in a mixture of toluene (20 mL) and water (0.8 mL). Addtricyclohexyl-phosphane (86 mg, 0.31 mmol) and palladium(II) acetate (50mg, 0.22 mmol) and stir the mixture at 70° C. for 3 h. Filter themixture through celite and wash the solids with EtOAc (30 mL). Collectand concentrate the filtrate and purify the residue by flashchromatography, using a linear gradient of 100% hexanes to 10%EtOAc/hexanes, to give the title compound as a clear oil 765 mg (84%):MS (ES) 314.1 (M+1)+.

Preparation 27 3-tert-Butyl-1H-indole

Add trifluoroacetic acid (TFA; 1.0 mL, 1.5 g, 13 mmol, 1.6 equiv) to asolution of indole (1.00 g, 8.54 mmol, 1 equiv) and tert-butyl alcohol(1.0 mL, 0.78 g, 10 mmol, 1.2 equiv) in anhydr 1,2-dichloroethane (40mL). The colorless solution slowly turns to brown while heating toreflux. After 1 h reflux, add more TFA (2 mL) and tert-butyl alcohol (2mL). After 16 h reflux, rotary evaporate the reaction solution (80° C.)giving a dark-brown solid. Transfer this material to a column of silicagel (235 mm×35 mm dia.) and elute (0-10% EtOAc/hex) the desired3-tert-butyl-1H-indole which co-elutes with a trifluoroacetatederivative of itself (3:1) yielding 284 mg of a brown oil. Elute thismaterial with (10% EtOAc/hex) again through a column of silica gel (125mm×25 mm dia.) yielding 124 mg (8.4%) of pure 3-tert-butyl-1H-indole asa light-orange crystalline solid. MS (m/z): 173.

Preparation 28 1-Bromo-1-methyl-cyclopentane

Stir 1-methylcyclopentanol (1.12 g, 11.2 mmol, 1 equiv) vigorously withaq HBr (48%; 5.0 mL, 7.4 g [0.48]=3.6 g HBr, 44 mmol, 4.0 equiv) for 30min. Separate the organic layer and extract the aqueous layer withhexanes (5 mL). Combine the organic layers, dry (anhydr MgSO₄) androtary evaporate (35° C.; some of the product distills) yielding 657 mg(36.0%) of 1-bromo-1-methyl-cyclopentane as a light-green liquid.

Preparation 29 3-(1-Methyl-cyclopentyl)-1H-indole

Add N,N-Diisopropylethylamine (890 μL, 660 mg, 5.1 mmol, 2.2 equiv) to amixture of indole (410 mg, 3.5 mmol, 2.0 equiv), tetrabutylammoniumiodide (860 mg, 2.3 mmol, 1.0 equiv), and zinc triflate (1000 mg, 2.8mmol, 1.2 equiv) in anhydrous toluene (10 mL). After stirring 15 min,add 1-bromo-1-methyl-cyclopentane (380 mg, 2.3 mmol, 1 equiv). After 15h, quench the reaction mixture with satd aq NH₄Cl (10 mL). Separate theorganic layer and extract the aqueous layer with Et₂O (10 mL). Dry thecombined organic layers (anhydr MgSO₄) and rotary evaporate (40° C.) togive 440 mg of material as a light-yellow oil. Transfer this material toa column of silica gel (125 mm×25 mm dia.) and elute (5-20% CH₂Cl₂/hex).Much desired product co-elutes with starting material indole. Transferthis material to a column of silica gel (80 mm×20 mm dia.) and elute(0-15% CH₂Cl₂/hex) to yield 99 mg (21%) of pure3-(1-methyl-cyclopentyl)-1H-indole as a colorless oil. MS (m/z): 199.

Preparation 30 1-[(Toluene-4-sulfonyl)-1H-indol-3-yl]-ethanone

Add 1.0 M t-BuOK (3.0 mL, 0.003 mol) to a stirring solution of 3-acetylindole (0.478 g, 0.0030 mol) in dry DMF (20 mL) under N₂ at ambienttemperature and stir for 30 min. Add toluenesulfonyl chloride to thissolution and stir the resulting mixture overnight. Pour the reactioninto EtOAc-H₂O, separate the organic layer and extract several timeswith H₂O wash with brine, dry (MgSO₄), filter, and evaporate on therotary evaporator. Chromatograph on the ISCO eluting with a gradienthexane-EtOAc (0-100%) over 30 minutes to give 0.73 g (78%) of the titlecompound as a solid: ¹H (CDCl₃).δ 7.8 (d, 1H), 8.2 (s, 1H), 7.9 (d, 1H),7.7 (d, 2H), 7.4 (m, 2H), 7.3 (d, 2H), 2.6 (s, 3H), 2.4 (s, 3H).

Preparation 31 2-[1-(Toluene-4-sulfonyl)-1H-indol-3-yl]-pro-pan-2ol

Add methyl magnesium bromide 3.0M (0.40 mL) to a stirring solution of1-[(toluenesulfonyl)-1H-indol-3-yl]-ethanone 0.31 g, 0.0010 mol) in dryTHF under N₂ at −30. A solid precipitates immediately. Allow thereaction mixture to warm to 0-10° C. and stir for 1 h. Cool the mixturein an ice bath and quench with a saturated solution of NH₄Cl. Dilutewith Et₂O, and separate the organic layer, wash with brine, dry (MgSO₄)filter. Concentrate to give an oil (0.36 g). Chromatograph using agradient hexane-EtOAc (0-100 over 30 minutes) to give 0.20 g (62%) ofthe desired as an off white solid: ¹H NMR (CDCl₃) δ 8.0 (d, 1H) 7.8 (m,3H), 7.45 (s, 1H), 7.4-7.2 (m, 4H), 2.4 (s, 3H), 1.7 (s, 6H).

Preparation 32 3-Isopropyl-1-(toluene-4-sulfonyl-1H-indole

Add TFA (1.35 mL, 0.0174 mol) to a stirring solution of2-[1-(Toluene-4-sulfonyindol-3-yl]-propan-2ol (0.358 g, 0.001 mol) inCH₂Cl₂ (20 mL) at 0° C. Stir the resulting mixture at 0-5° C. for 1 hand allow to warm to ambient temperature and stir for 1½ h. Pour thesolution into a mixture of saturated NaHCO₃—CH₂Cl₂. Separate the organiclayer, filter, and evaporate on the rotary evaporator to give 0.103 g ofthe desired compound: ¹H NMR (CDCl₃) δ 8.0 (d, 2H), 7.8 (d, 2H), 7.55(d, 1H), 7.3-7.2 (m, 5H), 3.1 (m, 1H), 2.38 (3H), 1.28 (d, 6H).

Preparation 33 3-Isopropyl indole

Add five molar NaOH (3.0 mL), 0.015 mol) to a suspension of3-isopropyl-1-(toluene-4-sulfonyl)-1H-indole 0.100 g, 0.032 mmol) inEtOH (6.0 mL) at ambient temperature and heat the resulting mixture andstir at 90° C. overnight. Dilute the mixture with H₂O (5.0 mL) andconcentrate on the rotary evaporatory. Extract the resulting suspensionwith Et₂O. Separate the organic layer, dry (MgSO₄) and filter. Evaporateto give the title compound 0.0387 (77%) as a yellow oil: ¹H NMR (CDCl₃)δ 7.88-7.82 (bs, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (t,1H), 7.0 (d, 1H), 3.3 (m, 1H), 1.43 (d, 6H).

Preparation 34 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid

Add to a 2 L 3-neck flask equipped with reflux condenser, thermometerand nitrogen inlet, 4-(3-iodo-indole-1-sulfonyl)-benzoic acid methylester (0.1 mol, 44.1 g), phenylboronic acid (0.12 mol, 22.35 g),1,1-bis(diphenylphosphino)ferrocene dichloropalladium (0.0025 mol, 2.04g), 2M sodium carbonate (140 ml) and 0.5 L THF. Heat the mixture toreflux under nitrogen for 2 hours. Remove THF under vacuum, and add MTBE(500 ml) and DI water (200 ml) to the residue. Filter the solutionthrough a pad of Celite, and wash with MTBE (500 ml). Separate theorganic layer and concentrate under vacuum to give a brown solid.Dissolve the solid in THF (250 ml). Add to this solution 5N NaOH (35 ml)dropwise over a 30 minute period. Stir the reaction at ambienttemperature for 3 hours, and quench with DI water (250 ml) and MTBE (250ml). Separate the water layer and back extract the organic layer with DIwater (250 ml). Combine the aqueous layers and wash with MTBE (500 ml).Stir the aqueous layer at ambient temperature and adjust the pH is to 1with concentrated HCl. Stir the slurry at ambient temperature for 2hours, filter and wash with DI water (500 ml). Dry the off-white, graysolid in vacuum oven at 65° C. for 16 hours to obtain 25.44 g. ¹H NMR(DMSO) 8.2 (d, 2H), 8.1 (m, 3H), 7.9 (d, 1H), 7.7 (d, 2H), 7.4 (m, 5H).MS (ES−)=376.2 (M−1). Anal. Calcd. For C₂₁H₁₅NO₄S: C, 66.8308; H,4.0060; N, 3.7112. found C, 66.54; H, 4.07; N, 3.20.

Preparation 35 4-(3-Isopropyl-indole-1-sulfonyl)-benzoic acid methylester

Add potassium tert butoxide 1.0 M (1.6 mL, 0.0016 mol) dropwise to astirring solution of 3-isopropyl indole (0.217 g, 00136 mol) in dry DMF(20 mL) under N₂ at ambient temperature. Stir the reaction mixture for30 minutes and add portionwise 4-chlorosulfonyl benzoic acid methylester (0.328 g, 0.0014 mol). The light brown reaction mixturedecolorizes immediately. Stir the resulting yellow solution overnight.Pour into a EtOAc-H₂O mixture (100 to 300 mL). Separate the EtOAc andsequentially extract with H₂O (3×250 mL), wash with brine, dry (MgSO₄),filter and evaporate giving 0.38 g. Chromatograph on the ISCO using agradient hexane-EtOAc (0-50%, 30 30 minutes) to give 0.249 g (51%) ofthe title compound as a waxy solid. Mass spectrum (m/e) (M+H) 358.1113.found (M+H) 358.1129.

Preparation 36 4-(3-Isopropyl-indole-1-sulfonyl)-benzoic acid

Add five molar NaOH (1.5 mL 0.0075 mol) to a stirring solution of4-(3-isopropyl-indole-1-sulfonyl)-benzoic acid methyl ester (0.230 g,0.00061 mol) in THF (10.0 mL) at ambient temperature under N₂. Stir theresulting mixture overnight Dilute with 5% NaHCO₃ (75 mL) and extractwith Et₂O. Separate the aqueous layer and acidify with 37% HCl. Extractthe resulting precipitate into EtOAc, wash with brine, dry (MgSO₄),filter and evaporate giving 0.187 g of the title compound as an offwhite solid: Mass spectrum (m/e) (M−H) 342.0800; Found (M−H) 342.0802.

Preparation 37 4-[3-(2-Fluoro-pyridin-3-yl)-indole-1-sulfon)]-benzoicacid

Reflux a mixture of 4-(3-iodo-indole-1-sulfonyl)-benzoic acid methyl(ester (1.33 g, 3.01 mmol, 1 equiv), 2-fluoropyridine-3-boronic acid(Frontier Scientific®; 0.47 g, 3.3 mmol, 1.1 equiv), sodium carbonate(2M in H₂O; 3.0 mL, 6.0 mmol, 2.0 equiv), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (62 mg, 0.080 mmol, 0.025 equiv) in THF (15 mL) under N₂for 2 h (reaction mixture turned very dark when heated). Rotaryevaporate the reaction mixture. Dissolve the resultant residue in Et₂O(15 mL) and wash with H₂O (5 mL). Back-extract the aqueous layer is withEt₂O (5 mL). Dry the combined organic layers with (anhydr Na₂SO₄), androtary evaporate (40° C.) giving the crude4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoic acid methylester as a brown foam. Dissolve this material in THF (10 mL) and add 5Maq NaOH (2 mL). After 18 h, add H₂O (25 mL) and Et₂O (25 mL). Separatethe aqueous layer and extract the organic layer with H₂O (25 mL).Combine the aqueous layers and wash with Et₂O (25 mL). Acidify thisaqueous layer with 1M aq HCl (8 mL) to pH 5 causing much precipitation.Extract this mixture with CHCl₃ (1×50 mL, 2×25 mL). Dry the combinedorganic layers (anhydr Na₂SO₄) and rotary evaporate (40° C.) yielding673 mg (56.3%) of4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoic acid as a brownpowder. MS (m/e): 396.94 (M+1); 394.99 (M−1).

Preparation 38 4-[3-(6-Fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoicacid

Prepare the title compound by a similar method described for4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzoic acid using4-(3-iodo-indole-1-sulfonyl)-benzoic acid methyl ester (1.33 g, 3.01mmol, 1 equiv), 2-fluoropyridine-5-boronic acid (Frontier Scientific®;0.47 g, 3.3 mmol, 1.1 equiv) to give 965 mg (80.8%) of brown powder. MS(m/e): 396.94 (M+1); 394.98 (M−1).

Preparation 39 4-(3-Cyclopropyl-indole-1-sulfonyl)-benzoic acid methylester

Add a solution of tetrabutylammonium fluoride (3.0 mL, 3.0 mmol; 1.0M inTHF) to a solution of 3-cyclopropyl-1-triisopropylsilanyl-1H-indole(0.76 g, 2.4 mmol) in THF (15.0 mL). Stir at RT for 15 min, concentrateto a viscous oil, and re-dissolve in Et₂O (50 mL). Wash the organicsolution with water (30 mL) and satd NaHCO₃ (30 mL). Dry, filter andconcentrate the organic solution and purify the residue by flashchromatography, using a linear gradient of 100% hexanes to 30%EtOAc/hexanes, to give the title compound as a light yellow oil stillcontaining triisopropylfluoride as an impurity. Use the materialdirectly in the next reaction without further purification.

Add potassium ter-t-butoxide (280 mg, 2.49 mmol) to a solution of theabove 3-cyclopropyl-1H-indole in DMF (10.0 mL). Treat the solution with4-chlorosulfonyl-benzoic acid methyl ester (590 mg, 2.51 mmol) and stirat RT for 2 h. Dilute the solution with EtOAc (30 mL) and wash withwater (20 mL) and satd NaHCO₃ (20 mL). Dry, filter and concentrate theorganic solution and purify the residue by flash chromatography, using alinear gradient of 100% hexanes to 20% EtOAc/hexanes, to give the titlecompound as a light yellow oil (505 mg, 59%, 2 steps). MS (ES) 355.9(M+1)+.

Preparation 40 4-(3-Cyclopropyl-indole-1-sulfonyl)-benzoic acid

Add lithium hydroxidemonohydrate (181 mg, 4.31 mmol) to a solution of4-(3-cyclopropyl-indole-1-sulfonyl)-benzoic acid methyl ester (505 mg,1.42 mmol) in 3:1 dioxane:water (6.0 mL). Stir the mixture at RT for 4h, dilute with water (80 mL) and add 1N HCl until mixture reaches pH 2.Collect the white solid by filtration and dry overnight under vacuum togive the title compound (450 mg, 93%). MS (ES) 341.9 (M+1)+, 340.1(M−1)−.

Preparation 414-[3-(4-Hydroxy-tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acidmethyl ester

[Note: Dry all glassware in an oven at 120° C. and assemble warm priorto reaction.] Equip a 5-L 3-neck roundbottom flask with an overheadstirrer, temperature probe, N₂ line, and septa and charge with4-(3-iodo-indole-1-sulfonyl)-benzoic acid methyl ester (159.0 g, 0.360mol). Introduce THF (1 L) via cannula and stir the solution and cool to−75° C. under N₂. Dry a dropping funnel as above and assemble on theflask and add 2 M cyclopentylmagnesium bromide in diethyl ether (200 mL,0.400 mol) to the dropping funnel via cannula. Add dropwise the solutionover 0.5 h and stir the resulting mixture for 0.5 h. Warm the mixture to0° C., stir an additional 0.5 h, cool back down to −10° C., and treatwith a solution of tetrahydro-4H-pyran-4-one (43.0 g, 0.429 mol) in THF(100 mL) add via cannula to a new previously dried dropping funnel. Addthe ketone over 0.5 h as to maintain the internal temperature below −10°C. Warm the solution to room temperature and stir for 1.5 h in theprocess. Quench the mixture under N₂ by the addition of aqueoussaturated ammonium chloride (1 L), separate layers, and dry the organiclayer over sodium sulfate. Concentrate to provide a dark oil anddissolve in MTBE (1 L). Addition of 0.5 L of hexanes provides a solidand allows the solid to stand overnight at room temperature. Filter thesolid, back-wash with 2:1 MTBE/hexanes (150 mL) to give a tan solid.Reslurry the solid in ethyl acetate (1 L), stir at room temperature for2 h, filter, dry (20 mm Hg, 50° C.) and found to be highly titlecompound (49.2 g, 33%); ¹H NMR (DMSO-d₆) δ 8.15 (m, 4H), 7.94 (d, J=8.2Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.60 (s, 1H), 7.36 (t, J=7.7 Hz, 1H),7.27 (t, J=7.7 Hz, 1H), 5.27 (s, 1H), 3.85 (s, 3H), 3.81 (m, 2H), 3.69(m, 2H), 2.06 (m, 2H), 1.78 (m, 2H); MS (ESI) m/z 398 (m+H, m−H₂O).[Note: Concentrate the filtrate from the ethyl acetate reslurry andfilter the resulting solid from methylene chloride/hexanes/ethyl etherto provide a second crop of alcohol of good quality, 32 g. Thus, theoverall yield is 81.2 g, 54%. Concentrate the initial filtrate from theMTBE/hexanes crystallization to an oil and addition of methylenechloride/hexanes/ethyl ether to provide a solid consisting majorly ofthe corresponding 3-protioindole analog, 28 g.

Preparation 42 4-[3-(Tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoicacid methyl ester

Add to a solution of4-[3-(4-hydroxy-tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acidmethyl ester (20.0 g, 48.19 mmol) in anhydrous methylene chloride (500mL) at room temperature, triethylsilane (20.0 mL, 125.19 mmol) andtrifluoroacetic acid (61.5 mL, 798.2 mmol). Stir the resulting solutionfor 1 h, concentrate, and obtain the oil and partition between ethylacetate (500 mL) and saturated sodium bicarbonate (500 mL). Dry theorganic layer over sodium sulfate, filter through a silica gel pad, andback-wash with ethyl acetate (400 mL). Concentrate the filtrate to lowvolume, add hexanes, and a separate the solid. Filter the solid and holdaside, 14 g. Concentrate the filtrate to low volume and add MTBE toprovide a second crop of crystals, filter and found identical by TLC(3:2 hexanes/ethyl acetate) to the original lot, 2.8 g. Combine the twolots and dry (20 mmg Hg, 40° C.) to provide one lot of highly pure titlecompound for subsequent hydrolysis (16.8 g, 87%); ¹H NMR (DMSO-d₆) δ8.10 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.57 (s,1H), 7.37 (t, J=7.7 Hz, 1H), 7.28 (t, J=7.1 Hz, 1H), 3.94 (m, 2H), 3.85(s, 3H), 3.50 (t, J=11.5 Hz, 2H), 3.03 (m, 1H), 1.86 (m, 2H), 1.70 (m,2H); MS (ESI) m/z 400 (m+H).

Preparation 43 4-[3-(Tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoicacid

Add to a suspension of4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzoic acid methylester (16.7 g, 41.83 mmol) in methanol (200 mL) with stirring THF (600mL). Treat the solution with 5N NaOH (23.5 ml, 2.8 eq.) and stir for 2 hat room temperature. Concentrate the solution to near dryness and treatwith 1N HCl (125 mL), a solid separates. Dilute to 500 mL total volumewith water, filter, back-wash with water, and dry (20 mm Hg, 60° C.) togive a resulting solid found to be pure title compound (15.8 g, 98%); ¹HNMR (DMSO-d₆) 13.57 (s, 1H), 8.08 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.68(d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.27 (t, J=7.1Hz, 1H), 3.95 (m, 2H), 3.47 (t, J=12.0 Hz, 2H), 3.03 (m, 1H), 1.85 (m,2H), 1.70 (m, 2H); MS (ESI) m/z 384 (m−H).

Preparation 44 4-(3-Cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acidmethyl ester

Add to a 2-L 3-neck round bottom flask equipped with overhead stirrer,N₂ line, and temperature probe 4-(3-Iodo-indole-1-sulfonyl)-benzoic acidmethyl ester (69.0 g, 0.156 mol) and anhydrous DMF (700 mL). Add to thestirring solution at room temperature cyclopentene (138.0 mL, 1.57 mol),palladium II acetate (1.8 g, 0.0 mmol), tetrabutylammonium chloride(43.5 g, 0.156 mol), and potassium acetate (46.0 g, 0.469 mol). Warm theresulting dark mixture at 60-65° C. for 16 h. Cool the reaction mixturefilter through celite, and back-wash with ethyl acetate (1 L). Partitionthe solution with 2×1 L of brine, dry the organic layer over sodiumsulfate, and chromatographe over flash silica gel (10% ethyl acetate inhexanes gradually increasing to 20% ethyl acetate in hexanes) to providepure title compound (48.3 g, 81%); MS (ESI) m/z 382 (m+H); ¹H NMR(DMSO-d₆) reveals the material to actually be a mixture of olefinic3-substituted cyclopentene indoles (approx. 1:1, with olefinic H's at5.8, 5.9, and 6.0 ppm integrating to 1H each), suitable as such forsubsequent hydrogenation.

Preparation 45 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid methylester

Dissolve 4-(3-cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methylester (2.2 g, 5.77 mmol) in ethanol (25 mL) and ethyl acetate (25 mL)and hydrogenate with 10% palladium on carbon (300 mg) at 33 psi for 16h. Filter the catalyst over celite and back-wash with 1:1 ethanol/ethylacetate (50 mL). Concentrate to give a dark solid and dissolve in 1:1ethyl acetate/hexanes (50 mL) and pass through a silica gel plug.Back-wash the plug with 1:1 ethyl acetate/hexanes (100 mL) andconcentrate the filtrate to an oil, which solidifies upon standing andfound to be pure title compound (2.0 g, 90%); ¹H NMR DMSO-d₆) δ8.10 (m,4H), 7.93 (d, J=8.2 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.36(t, J=7.1 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 3.84 (s, 3H), 3.16 (m, 1H),2.08 (m, 2H), 1.62 (m, 6H); MS (ESI) m/z 384 (m+H).

Preparation 46 C-(5-Fluoro-pyridin-3-yl)-methylamine

Add to a Parr Bottle 2,6 dichloro-3-cyano-5-fluoropyridine (5 g, 26.18mmol), ethanol (50 ml), concentrated hydrochloric acid (4.3 ml) and 10%Pd—C (0.5 g). Place on a Parr Shaker Apparatus under 36 psig hydrogenfor 6 hours at ambient temperature. Add potassium acetate (10.28 g,104.72 mmol) and continue under 48 psig hydrogen overnight at ambienttemperature. Filter the reaction over Celite and concentrate thefiltrate under vacuum to a residue. Add to the residue THF (100 ml).Filter the solid, and concentrate the filtrate under vacuum to give(5-Fluoro-pyridin-3-yl)-methylamine as a clear oil (6 g). ¹H NMR (DMSO):8.6 (d, 2H), 8.0 (d, 1H), 4.2 (s, 2H). MS (ES+)=127.5.

Preparation 47 C-(2-Fluoro-pyridin-3-yl)-methylamine hydrochloride

Add concentrated HCl (0.46 mL) to a suspension 2-fluoro-nicotinonitrile(0.34 g, 2.8 mmol) and 5% Pd/C (0.5 g) in methanol (10 mL) at RT. Stirsuspension under an atmosphere of hydrogen at 1 atm. For 6 hours. Filterreaction mixture and concentrate the filtrate. Add ether to the residue,bubble HCl gas through the suspension, filter precipitate, and dry togive the title compound (0.37 g, 82%). MS (ES) 127.1 (M+1)⁺. ¹H NMR (400MHz, DMSO) δ: 8.65 (brs, 3H), 8.24 (m, 1H), 8.16 (m, 1H), 7.41 (m, 1H),4.06 (m, 2H).

Preparation 48 C-(2-Fluoro-pyridin-4-yl)-methylamine hydrochloride

Following a method similar to C-(2-Fluoro-pyridin-3-yl)-methylaminehydrochloride, using 2-fluoro-isonicotinonitrile (0.65 g, 5.3 mmol),concentrated HCl (1.2 mL), and 5% Pd/C (1.2 g) to give the titlecompound (0.43 g, 50%). MS (ES) 127.1 (M+1)⁺.

Preparation 49 C-(4-Trifluoromethyl-pyridin-3-yl)-methylamine

Add Raney nickel (0.5 g) to a solution of4-trifluoromethyl-nicotinonitrile (1.0 g, 5.8 mmol) in ethanol saturatedwith ammonia (20.0 mL) and shake under hydrogen at 500 psi for 1 hour.Filter reaction, concentrate the filtrate, and dry the solid obtained togive the title compound (1.0 g, 98%). MS (ES) 177.0 (M+1)⁺.

Preparation 50 2-Fluoro-isonicotinonitrile

Treat a solution of 2-chloro-4-cyanopyridine (6.0 g, 43.5 mmol) andpotassium fluoride (7.56 g, 130.3 mmol) in 1-methyl-2-pyrrolidinone (20mL) with tetrabutylphosphonium bromide (14.8 g, 43.7 mmol) and heat to100° C. for 18 hours. Dilute with water and extract with EtOAc. WashEtOAc with water, brine, dry with Na₂SO₄, and concentrate to give thetitle compound (2.3 g, 43%). MS (ES) 123.1 (M+1)⁺. ¹H NMR (400 MHz,CHCl₃) δ 8.43 (d, 1H, J=5.2 Hz), 7.45 (m, 1H), 7.22 (m, 1H).

Preparation 51 2-Fluoro-nicotinonitrile

Add resin bound triphenylphosphine (4.0 g, 12.0 mmol) to a solution of2-fluoro-nicotinamide (0.6 g, 4.3 mmol) in dichloroethane (20.0 mL) andcarbon tetrachloride (20.0 mL). Reflux for 18 hours, cool to RT, filter,and concentrate the filtrate under vacuum. Purify by flash column onsilica gel eluting with 10-60% EtOAc in hexanes to give the titlecompound (0.34 g, 64%). MS (ES) 123.1 (M+1)⁺. ¹H NMR (400 MHz, CHCl₃) δ8.46 (m, 1H), 8.09 (m, 1H), 7.37 (m, 1H).

Preparation 52 2-Fluoro-nicotinamide

Add thionyl chloride (40 mL) to 2-fluoro-nicotinic acid (2.0 g, 14.3mmol), reflux for 18 hours, cool to RT, and concentrate under vacuum.Add benzene (100 mL) to the residue and bubble ammonia gas intosuspension for 3 hours. Stopper flask, stir for another 18 hours, andconcentrate. Add water to residue and extract with EtOAc. Wash EtOAcwith water, brine, then dry with Na₂SO₄, and concentrate under vacuum togive the title compound (0.6 g, 30%). MS (ES) 141.1 (M+1)⁺. ¹H NMR (400MHz, CHCl₃) δ 8.32 (d, 1H, J=4.5), 8.17 (m, 1H), 7.92 (brs, 1H), 7.79(brs, 1H), 7.44 (m, 1H).

Preparation 53 C-Pyrazin-2-yl-methylamine

In a Parr bottle, charge pyrazine-2-carbonitrile (1 g) in absoluteethanol (10 ml). Add 10% Pd—C (w/w, 0.4 g) and place on a ParrHydrogenation Apparatus under 50 psig hydrogen at ambient temperaturefor sixteen hours. Filter the mixture through a pad of Celite. Purifymaterial on SCX column. Use crude basic material in next step withoutfurther purification.

Preparation 54 C-Pyridazin-3-yl-methylamine

Hydrogenate pyridazine-3-carbonitrile using H₂, NH₃, MeOH, Raney Nickelat 40° C. and 60 psi. Filter crude material to remove catalyst. Dissolvein MeOH and purify on an SCX column to give basic material. Use materialcrude in the amide coupling without further purification.

Preparation 55 2-Methoxy-cyclohexylamine

Shake a mixture of o-anisidine (5.0 g, 41 mmol) and rhodium on carbon(5% Rh; 5.0 g) in AcOH (65 mL) under H₂ (60 psig) at 60° C. for 6 h.Filter the reaction mixture and rotary, evaporate the filtrate (75° C.).Dissolve this material in CHCl₃ (100 mL) and basifiy with satd aq NaHCO₃(50 mL). Dry the organic layer (Na₂SO₄) and rotary evaporate (40° C.) toyield 1.20 g of 2-methoxy-cyclohexylamine as a yellow oil.

Preparation 56 1-(4-Fluoro-phenyl)-piperidin-4-ylamine

Stir 4-Bromo-fluorobenzene (0.300 g, 1.714 mmole),4-Boc-amino-piperidine (0.411 g, 2.057 mmoles), sodium tert-butoxide(0.230 g, 2.4 mmole), Tris(Dibenzylideneaceton)Dipalladium (0.249 g,0.257 mmole), 2-(Di-t-butylphosphineol-biphenol (0.1278 g, 0.4285 mmole)in toluene until reaction is complete. Dilute solution with EtOAc andfilter. Concentrate the residue and purify via column chromatographywith a mixture of EtOAc and hexane. Stir the isolated material in TFAand remove solvent. Dilute the residue with methanol in the presence ofhydroxy resin until pH is basic. Decant solvent and concentrate to yield0.115 g of product (yield=34.5%). Mass Spectrum (m/e) 195.03 (M⁺).

Preparation 57 (R)-1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine

Prepare the title compound by a similar method described for1-(4-Fluoro-phenyl)-piperidin-4-ylamine above using(R)-2-ditertbutylphosphinobiphenyl (0.108 g, 0.362 mmole) to isolate0.136 g of solid material (Yield=52%) Mass Spectrum (m/e): 181.0 (M⁻).

Preparation 58 (S)-1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine

Prepared the title compound by a similar method described for1-(4-Fluoro-phenyl)-piperidin-4-ylamine above using(S)-2-ditertbutylphosphinobiphenyl (0.108 g, 0.362 mmole) to isolate0.090 g of solid material (Yield=34%) Mass Spectrum (m/e): 180.99 (M⁺).

Preparation 59 1-(4-Fluoro-phenyl)-azetidin-3-yl-amine

Prepare the title compound by a similar method described for1-(4-Fluoro-phenyl)-piperidin-4-ylamine above usingAzetidin-3-yl-carbamic acid tert-butyl ester (0.270 g, 0.186 mmole) toisolate 0.115 g of solid material (Yield=47%) Mass Spectrum (m/e): 168(M⁺).

Preparation 60 C-(1-Phenyl-piperidin-4-yl)-methylamine

Prepare as in methods described in J. of Med. Chem. 1999 vol. 42 (no 17)p 3342-3355.

Preparation 61 [1-(4-Fluoro-phenyl)-azetidin-3-ylmethyl]-carbamic acidtert-butyl ester

Prepare the title compound by a similar method described for[3-[(4-Fluoro-phenylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing azetidin-3-ylmethyl-carbamic acid tert-butyl ester (215 mg, 1.15mmol) to isolate 137 mg (42.3%) of light-yellow foam. MS (m/e): 225.00(M+1−C₄H₈).

Preparation 623-(tert-Butoxycarbonylamino-methyl)-azetidine-1-carboxylic acid methylester

Prepare the title compound by a similar method described for3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid methyl ester using azetidin-3-ylmethyl-carbamic acid tert-butylester (Beta Pharma; 559 mg, 3.00 mmol, 1 equiv) to isolate 686 mg(93.6%) of colorless oil.

Preparation 63 3-Aminomethyl-azetidine-1-carboxylic acid methyl ester

Prepare the title compound by a similar method described for(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing 3-(tert-butoxycarbonylamino-methyl)-azetidine-1-carboxylic acidmethyl ester (675 mg, 2.76 mmol) to isolate 399 mg (100%) oflight-yellow oil. MS (m/e): 144.98 (M+1).

Preparation 64 [1-(4-Fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester

Prepare the title compound by a similar method described forN-[1-(4-fluoro-phenyl)-azetidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamideusing 3-(tert-butoxycarbonylamino)pyrrolidine to isolate 341 mg (60.7%)of light-yellow crystalline solid. MS (m/e): 281.00 (M+1).

Preparation 65 1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine

Prepare the title compound by a similar method described for(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing [1-(4-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butylester (330 mg, 1.18 mmol) to isolate 204 mg (95.1%) of yellow oil. MS(m/e): 181.04 (M+1).

Preparation 66 5-Cyano-nicotinic acid methyl ester

Reflux a solution of methyl 5-bromonicotinate (2.16 g, 10.0 mmol, 1equiv) and copper(I) cyanide (1.79 g, 20.0 mmol, 2.0 equiv) in anhydrDMF (10 mL) for 15 h. After allowing to cool, filter the reactionmixture through Celite®, rinse with EtOAc (100 mL). A black precipitateforms in the filtrate. Wash the filtrate with salted H₂O (3×100 mL). Drythe organic layer (anhydr Na₂SO₄) and rotary evaporate (40° C.) giving546 mg (33.7%) of product as a light-yellow solid. Transfer thismaterial to a column of silica gel (80 mm×20 mm dia.) and elute (20-35%EtOAc/hex) to yield 501 mg (30.9%) of 5-cyano-nicotinic acid methylester as an off-white solid. MS (m/e): 163.07 (M+1).

Preparation 67 5-Hydroxymethyl-nicotinonitrile

Add lithium aluminum hydride (1.0M in THF; 1.5 mL, 1.5 mmol, 0.5 equiv)over a period of 3 min to a solution of 5-cyano-nicotinic acid methylester (479 mg, 2.95 mmol, 1 equiv) in anhydr THF (15 mL) and cool to−78° C. After 1 h while still at −78° C., quench the reaction with H₂O(60 μL), 5M aq NaOH (60 μL), and more H₂O (180 μL). Filter the reactionmixture through paper. Rotary evaporate the filtrate (40° C.) to give369 mg of material as a yellow solid. Transfer this material to a columnof silica gel (130 mm×25 mmdia.) and elute (2% MeOH/CH₂Cl₂) to yield 180mg of a mixture of ester, hemiacetal, and aldehyde as a yellow solid and45 mg (11%) of 5-hydroxymethyl-nicotinonitrile as a yellow solid. MS(m/e): 163.07 (M+1).

Preparation 68 5-Chloromethyl-nicotinonitrile

Add thionyl chloride (1 mL) to a solution of5-hydroxymethyl-nicotinonitrile (45 mg, 0.34 mmol, 1 equiv) in anhydrCH₂Cl₂ (1 mL). After 20 min, basify the reaction with satd aq NaHCO₃ (12mL). Extract this mixture with Et₂O (2×5 mL). Dry the combined organiclayers (anhydr MgSO₄) and rotary evaporate (40° C.) to yield 4.9 mg(9.6%) of 5-chloromethyl-nicotinonitrile as a yellow film. MS (m/z):152.

Preparation 69 5-Aminomethyl-nicotinonitrile

Dissolve 5-chloromethyl-nicotinonitrile (4.9 mg, 0.032 mmol) in 2.0M NH₃in MeOH (1 mL). Transfer this solution to a pressure tube. Heat thereaction solution at 80° C. for 2 h. Rotary evaporate the reactionsolution (40° C.) to yield 5.1 mg of crude 5-aminomethyl-nicotinonitrileas a yellow oil. MS (m/e): 134.00 (M+1).

Preparation 70 Methanesulfonic acid tetrahydro-furan-3-ylmethyl ester

Add triethylamine (6.0 mL, 4.4 g, 43 mmol, 2.1 equiv) to a solution oftetrahydro-3-furanmethanol (2.0 mL, 2.1 g, 21 mmol, 1 equiv) andmethanesulfonic anhydride (3.7 g, 21 mmol, 1.0 equiv) in anhydr CH₂Cl₂(100 mL). After stirring 20 h, wash the reaction solution with 1 M aqHCl (100 mL). Dry the organic layer (anhydr MgSO₄) and rotary evaporate(40° C.) to yield 2.77 g (74.0%) of methanesulfonic acidtetrahydro-furan-3-ylmethyl ester as a light-yellow liquid.

Preparation 71 3-Azidomethyl-tetrahydro-furan

Add sodium azide (1.5 g, 23 mmol, 1.5 equiv) to a solution ofmethanesulfonic acid tetrahydro-furan-3-ylmethyl ester (2.76 g, 15.3mmol, 1 equiv) in anhydr DMF (10 mL). Heat the reaction mixture at 50°C. for 16 h. Dilute the reaction mixture with H₂O (100 mL) and extractwith Et₂O (2×50 mL). Wash the combined organic layers with H₂O (2×50mL), dry (anhydr Na₂SO₄), and rotary evaporate (40° C.) to yield 1.20 g(61.6%) of 3-azidomethyl-tetrahydro-furan as a nearly-colorless liquid.

Preparation 72 (Tetrahydro-furan-3-yl)-methylamine

Stir a mixture of 3-azidomethyl-tetrahydro-furan (1.19 g, 9.36 mmol, 1equiv) and palladium on carbon (10% Pd; 120 mg) in EtOH (20 mL) under H₂(1 atm) for 18 h. Filter the reaction mixture through Celite® and rotaryevaporate the filtrate (40° C.) to yield 777 mg (82.1%) of crude(tetrahydro-furan-3-yl)-methylamine as a nearly-colorless liquid.

Preparation 73 4-Aminomethyl-benzonitrile

Stir 4-bromomethyl-benzonitrile (2.0 g, 0.010 mmoles) in sealed vesselin a solution of 2N ammonia in methanol at 80° C. until completion.Reduce solvent in volume. Dissolve residue in ethyl acetate and washwith 1N HCl. Basify aqueous layer with 5N NaOH. Extract aqueous layerinto dichloromethane. Dry organic layer over MgSO₄ and reduce in volumeto isolate 0.223 g. Yield=16.8%. Mass Spectrum (m/e): (M⁻).

Preparation 74 C-(Tetrahydro-pyran-2-yl)-methylamine

Heat 2-(bromomethyl)tetrahydropyran (2.0 g, 11.16 mmoles), sodium azide(1.088 g, 65.01 mmoles), and DMF to 50° C. with stirring and untilreaction is complete. Dilute the reaction mixture with Et₂O and washwith water once. Extract water layer with ether. Combine organicportions and dry over MgSO₄ and reduce in volume. Dilute residue ethanoland introduce to 10% Palladium (0.500 g) on carbon in the presence ofhydrogen until reaction is complete. Remove palladium on carbon viafiltration and concentrated to isolate 0.723 g. Yield=56%.

Preparation 75 3-Amino-pyrrolidine-1-carboxylic acid methyl ester

Add methyl chloroformate (460 μL, 560 mg, 6.0 mmol, 3.0 equiv) to asolution of 3-(tert-butoxycarbonylamino)pyrrolidine (TCI; 373 mg, 2.00mmol, 1 equiv) and triethylamine (1.1 mL, 800 mg, 7.9 mmol, 3.9 equiv)in anhydr CH₂Cl₂ (4 mL). Vigorous gas evolution, a slight exotherm, andprecipitation can occur. After stirring 30 min, rotary evaporate thereaction mixture (60° C.). Dissolve the resultant material in MeOH toquench any residual chloroformate and rotary evaporate the solution (60°C.). Add trifluoroacetic acid (5 mL) to this material causing gasevolution. Rotary evaporate the reaction solution (40° C.; azeotroping2× with MeOH). Resultanting in a yellow oil then dissolve in MeOH (30mL) and add hydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 9.3 g) tofree-base the amine. Filter the mixture and evaporate the filtrate byrotary (40° C.; azeotroped 2× with CH₂Cl₂) to yield 914 mg (300%) ofcrude product as a light-brown oil. Mass spec indicates desired productis present. Absorb this oil to an SCX column (20 g) activated with 10%AcOH/MeOH. Push MeOH through the column to elute any non-amine material.Elute the product with 2.0 M NH₃ in MeOH to yield 269 mg (93.2%) of3-amino-pyrrolidine-1-carboxylic acid methyl ester as a yellow oil.

Preparation 77N-(4-Fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide

Dissolve indole (2.93 g 0.025 mole) in 10 ml DMF. Cool the solution inan ice-water bath. Add potassium-t-butoxide (3.08 g, 0.0275 mole) and 10ml DMF. Stir in an ice-bath for 22 minutes. Add iodine (7.61 g, 0.03mole) and stir in an ice-bath for 12 minutes. Add the second shot ofpotassium-t-butoxide (3.08 g, 0.0275 mole) and 10 ml DMF. Add theappropriate sulfonyl chloride,4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride, (9.01 g, 0.0275mole) and 10 ml DMF. Stir at ambient temperature for 16 hours. Quenchthe reaction with 100 ml water, and extract with ethyl acetate (3×150ml). Wash the organics with sodium metabisulfate (10 g in 100 ml water),water (3×200 ml) and saturated brine (1×200 ml). Concentrate theorganics and purify over silica gel using 20% ethyl acetate in heptaneto obtain 6.96 g (yield=52.2%) of the desired product as an off-whitesolid: ¹H NMR (DMSO): 9.2 (t, 1H), 8.1 (m, 3H), 8.0 (m, 3H), 7.4 (m,5H), 7.1 (m, 2H), 4.4 (d, 4H). MS (ES−)=532.91 (M−1).

Preparation 78N-(4-Fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-sulfonyl]-benzamide

Combine N-(4-fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (19g, 35.65 mmol), bis pinnacolborane (10.86 g, 42.78 mmol), potassiumacetate (10.49 g, 106.95 mmol), PdCl₂(dppf)₂ (2.92 g, 3.57 mmol) in DMF(125 ml). Heat the mixture to 100° C. under nitrogen for 5 hours. Coolthe mixture to ambient temperature and quench with ethyl acetate (200ml) and water (200 ml). Filter the mixture through Celite. Separate thelayers and wash the organics with water (3×200 ml) and a saturated brinesolution (200 ml). Dry the organics over magnesium sulfate, filter andconcentrate to an oil which was crystallized with ether (200 ml). Filterthe white solid and dry in a vacuum oven at 50° C. overnight to provide(5.6 g) as a white solid. Mp 158-160° C.; ¹H NMR (DMSO): 9.2 (t, 1H),8.1 (m, 3H), 8.0 (m, 3H), 7.4 (m, 5H), 7.1 (m, 2H), 4.4 (d, 4H), 1.3 (s,12H). MS (ES)=533.4 (M−1).

Preparation 79 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid

Add to a stirring solution of4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid methyl ester (2.0 g,5.22 mmol) in THF (50 mL) and MeOH (25 mL), 5N NaOH (3 mL, 2.9 eq.).Stir the solution for 2 h at room temperature and the remove solvents togive a paste. Treat the paste with 1N HCl (25 mL) and a solid results.Dilute further with water (50 mL). Filter the solid, back-wash withwater, and dry (20 mm Hg, 60° C.) to provide the pure title compound(1.63 g, 84%); ¹H NMR (DMSO-d₆) δ 8.06 (m, 4H), 7.93 (d, J=8.2 Hz, 1H),7.63 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.37 (t, J=7.7 Hz, 1H), 7.28 (t,J=7.7 Hz, 1H), 3.17 (m, 1H), 2.08 (m, 2H), 1.69 (m, 6H); MS (ESI) m/z368 (m−H).

Preparation 804-(3-Chloro-indazole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

Dissolve 3-chloro-1H-indazole (120 mg, 0.79 mmol) and4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (114 mg, 0.35mmol) in CH₂Cl₂ (2.0 mL) and treat with Et₃N (50 L, 0.36 mmol). Stir thesolution for 1 h at RT, then dilute with additional CH₂Cl₂ (20.0 mL) andwash with satd aq. NaHCO₃ (15 mL). Dry, filter, and concentrate theorganic phase and purify the crude material by flash chromatography(100% hexanes to 50% EtOAc/hexanes linear gradient) to give the titlecompound (129 mg, 83%) as a white foam. MS (ES+) 443.9 (M+1)⁺, (ES⁻)442.0 (M−1)⁻. ¹H NMR (400 MHz, CDCl₃): δ 8.17 (d, 1H, J=8.3), 8.03 (d,2H, J=8.2), 7.83 (d, 2H, J=8.9), 7.64 (m, 2H), 7.41 (t, 1H, J=7.4), 7.27(m, 2H), 7.01 (t, 2H, J=8.9), 6.31 (br s, 1H), 4.57 (d, 2H, J=5.9).

Preparation 81 2-Phenyl-azetidine

Dissolve 4-phenyl-azetidin-2-one (1.0 g, 4.28 mmol) in anhydrous THF (20mL) and treat with 1.0 M solution of lithium aluminum hydride (8.57 mL,2.0 equiv.) at room temperature. Stir for 15 h, cool to 0° C. in an icebath and quench with 8.5 mL 1.0 M NaOH then 8.5 mL H₂O. Filter resultingsolution through celite with additional EtOAc, dry with MgSO₄, filterand evaporate to yield a milky white oil that solidifies upon standing.Use 2-Phenyl-azetidine without further purification.

Preparation 82 4-(3-Iodo-indole-1-sulfonyl)-benzoic acid methyl ester

Slurry 250 g of 4-sulfobenzoic acid in 750 ml thionyl chloride. Add 0.5ml DMF, and heat the mixture to reflux for 6 hours. Add 2 L of tolueneand azeotropically remove the thionyl chloride. Cool the mixture toambient temperature and filter. Concentrate the filtrate under vacuum togive an oil which crystallizes upon standing. To obtain 222 g of4-Chlorosulfonyl-benzoyl chloride as a low melting solid.

In a 22 L RBF, charge 4-Chlorosulfonyl-benzoyl chloride (990 g, 4.159mole) in 8.3 L THF and cool to −78° C. In an addition funnel chargetriethylamine (588 ml, 4.159 mole), methanol (168 ml, 4.159 mole), DMAP(5 g, 0.041 mole) and 4 L THF; add this solution dropwise to thereaction keeping the exotherm <−70° C. over 5 hours. After the additionis complete, stir the reaction in a cold bath overnight. Filter thereaction and rinse with 3×500 ml THF. Concentrate under vacuum thefiltrate to give a yellow solid. Dissolve the solid in 7 L EtOAc and 7 L1N HCl. Separate the organic layer and wash with 5 L brine. Dry theorganics over Na₂SO₄, filter and concentrate under vacuum to give awhite solid, 4-Chlorosulfonyl-benzoic acid methyl ester. Yield=93.1%(906 g).

In a 22 L RBF, charge indole (181 g, 1.545 mole) and 800 ml DMF. Cool to<10° C. in an ice-water bath. Add the first shot of potassium-t-butoxide(190.4 g, 1.70 mole). Exotherm to 18.5° C. Rinse with 400 ml DMF. Stir30 minutes while cooling back to <10° C. Dissolve Iodine (470.6 g) in400 ml DMF and charge to the addition funnel. Add this solution dropwiseto the reaction over 30 minutes. Keeping the temperature <10° C. Stir at<10° C. for 2.5 hours. Add the second shot of potassium-t-butoxide(190.4 g, 1.70 mole) and rinse with 400 ml DMF. Stir 30 minutes whilecooling to 10° C. (and add 4-Chlorosulfonyl-benzoic acid methyl esterall at once. Exotherm to 28° C. Rinse with 400 ml DMF. Cool to <10° C.and then stir to ambient temperature overnight. Add 6 L DI water atambient temperature. Exotherm to 31° C. and reaction is thick withsolids. Add 5 L EtOAc and stir 15 min. Filter the solids (which is theproduct). Obtain 315.1 g white solid as the first crop. Separate thefiltrate from the first crop, and extract the aqueous layer 2×3 L EtOAc.Combine all the organics and wash 2×625 g of sodium hydrogensulfite in 4L DI water and 2×3 L DI water and 1×3 L Brine. Dry organics over Na₂SO₄,filter and rinse with EtOAc. Remove the organics under vacuum to give anorange-yellow solid slurry solid in 4 L ether overnight to give a secondcrop of product 240 g. Total yield=81.4% (555.1 g). MS (EI) m/z 440.9(M+H).

Preparation 83 5-Chloro-2-cyanopyridine

Add in a 22-L 3-neck round bottom equipped with overhead stirrer, refluxcondenser, and thermometer, N,N-dimethylacetamide (DMAC, 6 L),2,5-dichloropyridine (347.0 g, 2.34 mol), zinc cyanide (138.0 g, 1.17mol), bis(diphenylphosphino)dipalladium II CH₂Cl₂ complex (DPPF, 20.8 g,0.02 mol), and zinc dust (1.6 g, 0.02 mol). Slowly warm the reactionmixture to 160° C. As the temperature reaches 160° C., an exotherm(controllable) may result and the internal temperature may rise to180-185° C. Remove the heat from the dark solution and cool the mixtureslowly cool to room temperature. Extract the bulk reaction mixture bytaking 2 L of the dark solution, diluting with brine (2 L), filteringover celite, and addition of ethyl acetate (4 L). Repeat the process 3times to extract all material, and dry the combined organics overmagnesium sulfate. Cautious concentration at 25-30° C. might give a darkliquid. (Note: Product volatility maybe observed at higher temperaturesso the temperature upon concentration is kept low in all steps.) Stirthe liquid and add water (5 L), resulting in a solid After 1 h, filter,and back-wash with water (2 L). Dry the filter cake to give 215 g ofcrude product. Extract the aqueous filtrate with ethyl ether (8 L). Drythe organics over magnesium sulfate and concentrate to provide 51 g ofcrude product. Combine with the 215 g lot and purify by chromatographyover silica gel (biotage 150; eluting with 5% ethyl acetate in hexanesincreasing to 10% ethyl acetate in hexanes) to provide a white solid ofpure title compound (193 g, 59%); ¹H NMR (CDCl₃) δ 8.68 (d, J=2.0 Hz,1H), 7.84 (dd, J=2.7, 8.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H).

Preparation 84 2-Cyano-5-fluoropyridine

Add in a 5-L 3-neck roundbottom equipped with overhead stirrer, refluxcondenser, thermometer, and N₂ line, 5-chloro-2-cyanopyridine (193.0 g,1.39 mol) and 1-methyl-2-pyrrolidinone (NMP, 2 L). Heat the mixture andstir at 210-220° C. for 4 h. Cool the reaction mixture to roomtemperature, stir overnight, and filter. Wash the filter cake with ethylether (1 L). Extract the filtrate with water (6 L) and ethyl ether (3×5L). Combine the organics and back-extract with water (8 L) and dry overmagnesium sulfate. Concentrate at 25-30° C. to give an oily semi-solid,193 g. Chromatograph over flash silica gel (5% ethyl acetate in hexanesgradually increasing to 10% ethyl acetate in hexanes) to provide thetitle compound as a white solid. Dissolve the solid in ethyl ether,filter, and add hexanes. Concentrate to low volume to provide a primarycrop of pure title compound, 60 g. Repeat the process of crystallizationon the filtrate to provide a second crop of highly pure title compound,24.0 g. (Concentrate the final filtrate to a white solid of product ofgood quality, and re-chromatograph, conditions as above, to provide anadditional 38.6 g of material.) Obtain a total yield of title compoundof 122.4 g, 72%; ¹H NMR (CDCl₃) δ 8.59 (d, J=3.0 Hz, 1H), 7.75 (m, 1H),7.55 (m, 1H).

Preparation 85 2-Aminomethyl-5-fluoropyridine (dihydrochloride)

Combine a mixture of 2-cyano-5-fluoropyridine (63.2 g, 0.52 mol), 22.5 gof Raney nickel, and ethanol (1.5 L) saturated with ammonia andhydrogenate at 500 p.s.i. and 70° C. for 16 h. Chromatograph the darkpurple liquid over flash silica gel (methylene chloride/methanol/ammoniahydroxide—95:4.5:0.5) to give, after concentration at 25-30° C., ayellow liquid of the pure desired free base, 25.0 g (44%); ¹H NMR(DMSO-d₆) δ 8.43 (d, J=2.9 Hz, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.77 (s,2H), 2.10 (br, 2H); MS (ESI) m/z 127 (m+H). Add to a solution of thefree base (20.0 g, 159.0 mmol) in 150 ml of 1,4-dioxane, 4N HCl indioxane (150 mL, 3.8 eq.) and a white solid separates immediately.Dilute the solid with ethyl ether (300 mL) and filter. Dry the productat 20 mm Hg, 60° C., to give the pure dihydrochloride title compound,30.0 g (95%); ¹H NMR (DMSO-d₆) δ 8.61 (d, J=2.9 Hz, 1H), 8.50 (brs, 3H),7.82 (m, 1H), 7.62 (m, 1H), 7.50 (br, 1H), 4.18 (m, 2H); MS (ESI) m/z127 (m+H, free base).

Preparation 87 N-Pyridin-2-yl-N′-styryl-hydrazine

React Pyridin-2-yl-hydrazine and Phenyl-acetaldehyde under literatureconditions (Azaindoles. I. Preparation of 7-azaindoles by thermalindolization of 2-pyridylhydrazones. Canadian Journal of Chemistry(1966), 44(21), 2455-9) to give N-Pyridin-2-yl-N′-styryl-hydrazine (10g, 100% yield crude material) Mass Spectrum (m/e): 211.96 (MH+).

Preparation 88 3-Phenyl-1H-pyrrolo[2,3-b]pyridine

React N-pyridin-2-yl-N′-styryl-hydrazine according to publishedliterature conditions (Azaindoles. I. Preparation of 7-azaindoles bythermal indolization of 2-pyridylhydrazones. Canadian Journal ofChemistry (1966), 44(21), 2455-9) to give3-Phenyl-1H-pyrrolo[2,3-b]pyridine (2.5 g, 45% yield) as a dark solid.Mass Spectrum (m/e): 194.96 (MH+).

Preparation 91 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoicacid methyl ester

Via addition funnel slowly add over 0.5 hours the 2M EtOEt solution ofcyclopropyl magnesium bromide (2.16 g, 6.23 ml, 12.46 mmol, 1.1 eq) tothe −78° C. THF solution (30 ml) of 4-(3-Iodo-indole-1-sulfonyl)-benzoicacid methyl ester (5 g, 11.33 mmol, 1.00 eq). Stir for 2 hours and thenwarm to 0° C. Stir for 0.5 hours. Recool to −10° C. and then slowly adda THF solution (3 ml) of cyclohexanone (1.298 g, 13.03 mmol, 1.15 eq).Stir for 15 min and warm to room temperature. Stir for 1.5 days. Quenchreaction with saturated aqueous ammonium chloride, remove organics onrotovap, and add EtOAc to crude mix. Extract product into organics,separate organics, dry over MgSO₄, and concentrate on rotovap to givecrude product as an oil. Purify by silica gel chromatography to give4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester(948 mg, 20% yield).

Preparation 92 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methylester

Under N₂, add triethylsilane (676 mg, 0.929 ml, 5.82 mmol, 2.6 eq)followed by trifluoroacetic acid (4.08 g, 2.7 ml, 35.79 mmol, 16.0 eq)to a CH₂Cl₂ solution (20 ml) of4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester(9.25 mg, 2.24 mmol, 1 eq). Stir for 1.5 hours and then remove volatileson rotovap. Add EtOAc to crude mix and workup with sat aqueous sodiumbicarbonate. Extract product into organics, separate organics, dry overMgSO₄, and concentrate on rotovap to give crude product as a pink oil.Purify by silica gel chromatography to give4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg,87% yield) as a white solid. Mass Spectrum (m/e): 397.99 (MH+).

Preparation 93 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid

Add 5N sodium hydroxide (1.17 ml, 3 eq) to a solution of4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg,1.95 mmol, 1 eq) dissolve in a mixture of 10 ml THF and 5 ml MeOH. Stirfor 1.5 hours. Remove solvent on rotovap and add 1 N HCl. Dissolve thesolid that crashes out of solution in EtOAc. Extract product intoorganics, separate organics, dry over MgSO₄, and concentrate on rotovapto give 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid (646 mg, 86%yield) as a white solid.

Preparation 944-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid methylester

Add potassium tertbutoxide (368 mg, 3.28 mmol, 1.1 eq) to a 3 ml dioxanesolution of 3-(3,3-difluoro-cyclopentyl)-1H-indole (660 mg, 2.98 mmol,1.0 eq) under N₂. Stir solution for 5 minutes. Add4-Chlorosulfonyl-benzoic acid methyl ester 117 mg, 0.497 mmol, 1.1 eq).Stir reaction for 4 hours at room temperature. Strip reaction of solventand purify by silica gel chromatography to give4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid methylester (466 mg, 37% yield).

Preparation 954-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid

Add aqueous sodium hydroxide (5N, 0.72 ml, 3 eq) to a solution of4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid methylester (500 mg, 1.20 mml, 1 eq) in 5 ml THF, 2.5 ml MeOH. Stir reactionat room temperature for 2 hours. Remove solvent on rotovap and add 1NHCl and EtOAc. Extract products into organics, separate organics, andthen dry organics with MgSO4. Filter off drying agent, and removeorganics on rotovap to give4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid (450 mg,92% yield) which was used without further purification.

Preparation 96 3-Piperidin-1-yl-1-triisopropylsilanyl-1H-indole

Dissolve piperidine (1.28 mL, 12.9 mmol) in THF (10 mL) and treat withlithium bis(trimethylsilyl)-amide (1.0M in THF, 11.2 mL, 11.2 mmol). Tothe above solution add 3-bromo-1-triisopropylsilanyl-1H-indole (TCI-US,3.04 g, 8.62 mmol),(2′-dicyclohexyl-phosphanyl-biphenyl-2-yl)-dimethyl-amine (88 mg, 0.22mmol), and Pd₂ dba₃.CHCl₃ (225 mg, 0.22 mmol). Heat the red solution to70° C. for 4 h then cool to RT and concentrate. Purify the crudematerial by flash chromatography, using a linear gradient of 100%hexanes to 40% EtOAc/hexanes, to give the title compound (837 mg, 27%).MS (ES⁺) 357.2 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.61 (d, 1H, J=8.4),7.41 (d, 1H, J=8.4), 7.07 (m, 2H), 6.68 (s, 1H), 3.03 (m, 4H), 1.79 (m,4H), 1.65 (septet, 3H, J=7.7), 1.58 (m, 2H), 1.12 (d, 18H, J=7.1).

Preparation 97 3-Piperidin-1-yl-1H-indole

Add nBu₄NF (1.0M in THF, 3.2 mL, 3.2 mmol) to a solution of3-piperidin-1-yl-1-triisopropylsilanyl-1H-indole (835 mg, 2.34 mmol) inTHF (10 mL). Stir the red solution at RT for 1 h, then dilute with EtOAc(40 mL) and wash with satd NaHCO₃ (20 mL). Dry, filter, and concentratethe organic solution then purify the crude material by flashchromatography, using a linear gradient of 100% hexanes to 40%EtOAc/hexanes. Obtain the title compound (347 mg, 74%) as a grey solid.MS (ES⁺) 201.1 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.65 (d, 1H, J=8.1),7.59 (br s, 1H), 7.29 (d, 1H, J=8.4), 7.16 (t, 1H, J=7.5), 7.06 (t, 1H,J=7.9), 6.70 (s, 1H), 3.03 (m, 4H), 1.80 (m, 4H), 1.59 (m, 2H).

Preparation 98 4-Fluoro-3-methoxy-benzylamine

Add 4-fluoro-3-methoxy-benzonitrile (2 g, 0.01 mol), 10% palladium oncarbon (0.400 g) and glacial acetic acid (120 ml) to a pressure vessel.Purge the reaction vessel with nitrogen, purge the reaction vessel withhydrogen, pressurize the reaction mixture with hydrogen (415 Kpa), sealthe vessel, and agitate the reaction. After 8 hours stop the agitation,vent the excess hydrogen from the vessel and purge the vessel withnitrogen. Filter the reaction mixture to remove the 5% palladium oncarbon and return the filtrate for product isolation. Concentrate thecrude solution, re-dissolve in CH₂Cl₂ (80 mL) and washe with 5N NaOH (35mL). Separate the organic and aqueous phases and extract the aqueouswith additional CH₂Cl₂ (20 mL). Combine the organic solutions, dry,filter and concentrate to give the crude material 2.08 g (100%). Thetitle compound as the major product (Rf=0.12, 10% MeOH/CH₂Cl₂) is usedwithout further purification. MS (ES⁺) 156.1 (M+1)⁺. ¹H NMR (400 MHz,CDCl₃): δ 7.01 (dd, 1H, J=8.2, 11.4), 6.95 (dd, 1H, J=2.1, 8.4), 6.80(m, 1H), 3.89 (s, 3H), 3.82 (s, 2H), 1.54 (br s, 2H).

Preparation 99 4-(4-Fluoro-3-methoxy-benzylcarbamoyl)-benzenesulfonylchloride

Dissolve 4-chlorosulfonyl-benzoyl chloride (3.18 g, 13.3 mmol) in THF(25 mL) and cool to −78° C. Slowly add a pre-mixed solution of4-fluoro-3-methoxybenzyl-amine (1.91 g, 12.3 mmol), Et₃N (1.64 mL, 11.8mmol), and DMAP (150 mg, 1.23 mmol) in THF (25 mL) to the above cooledsolution over 1 h. Stir the resulting mixture at −78° C. for 1 h, thenwarm to RT and stir for 4 h. Remove all solids by filtration and washwith THF (5 mL). Concentrate the filtrate and re-dissolve the crudematerial in EtOAc (30 mL) and wash with 1N HCl (30 mL). Separate theorganic and aqueous layers and extract the aqueous phase with additionalEtOAc (30 mL). Combine the organic solutions dry, filter, andconcentrate. Purify the crude material by flash chromatography, using alinear gradient of 100% hexanes to 40% EtOAc/hexanes) to give the titlecompound as a white solid (1.36 g, 28%). MS (ES⁻) 356.1 (M−1)⁻. ¹H NMR(400 MHz, CDCl₃): δ 8.11 (d, 2H, J=8.3), 8.00 (d, 2H, J=8.8), 7.05 (dd,1H, J=8.2, 11.1), 6.96 (dd, 1H, J=1.9, 8.0), 6.86 (m, 1H), 6.44 (br s,1H), 4.61 (d, 2H, J=5.7), 3.88 (s, 3H).

Preparation 100 Cyclopentyl-(2-fluoro-phenyl)-methanone

Stir 2-Fluorobenzonitrile (5.0 g, 41.01 mmole) in 80 ml of THF with a 2molar cyclopentyl magnesium bromide THF solution (20.51 ml, 41.01 mmole)and CuBr (0.100 g, 0.697 mmole) for 15 hrs at 60° C. under argon gas.Add a 15% solution of sulfuric acid to the reaction at 0° C. and stirfor 15 hrs. Extract the reaction mixture three times with diethyl ether.Combine organic layers and dry over MgSO₄ and concentrate. Purifyresidue via column chromatography using mixture of Ethyl Acetate andhexanes; to give 3.085 grams. Yield 40% MS (ES)=192.15 (M+1)+.

Preparation 101 3-Cyclopentyl-1H-indazole

Dissolve Cyclopentyl-(2-fluoro-phenyl)-methanone (2.5 g 13.005 mmoles)in hydrazine (20 ml) heat to 130° C. for 72 hrs. Cool mixture to 0° C.Filter the precipitate and wash with cold water to give the titlecompound: 2.171 g (yield=89%) MS ES+187.12:MSES− 185.22.

Preparation 102 4-(3-Cyclopentyl-indazole-1-sulfonyl)-benzoic acidmethyl ester

Combine 3-Cyclopentyl-1H-indazole (2.168 g 11.640 mmole) withtriethylamine (3.526 g, 34.92 mmoles) in 50 mls of dichloromethane.Dissolve 4-Chlorosulfonyl-benzoic acid methyl ester (4.085 g, 17.460mmole) in dichloromethane 50 ml and add drop wise to solution at 0° C.Stir the reaction is for 12 hrs. Dilute the reaction and wash withNaHCO₃. Dry organic layer over MgSO₄ and concentrate. Purify the residuevia column chromatography with a mixture of ethyl acetate and hexanes toisolate 2.046 g (Yield=48.5%) of the title compound: MS ES+385.3.

Preparation 103 4-(3-Cyclopentyl-indazole-1-sulfonyl)-benzoic acid

Combine 4-(3-Cyclopentyl-indazole-1-sulfonyl)-benzoic acid methyl ester(2.045 g, 5.325 mmoles) in 50 ml of THF. Add 3 ml of 5 N NaOH and allowto stir for 15 hrs. Make the reaction acidic with HCl and extract intodiethyl ether. Dry organic layer over MgSO₄ and concentrate to isolate1.243 g (Yield=63%) of the title compound: MS ES+ 369.47; MS ES− 369.46.

Preparation 104 (S)-1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine

Combine (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.741 mmole)1-bromo-4-Fluorobenzene (1.45 mmole), Pd₂dba (0.217 mmole), NaOtBu (2.03mmole), 2-di-t-butylphospineolbiphenyl (0.362 mmole) in 30 ml of tolueneand stir at 80° C. Dilute solution with ethyl acetate and filter.Concentrate the solution. Purify the residue via column chromatographywith a mixture of ethyl acetate and hexanes and add a mixture ofmethanol and Trifluoro acetic acid and stir for 1 hr at 0° C.Concentrate the reaction and dissolve in methanol in presence of hydroxyresin until pH is 10. Filter the solution and concentrate to isolate0.136 of title compound yield=52 MS ES−=182.0.

Preparation 105 Azetidin-3-yl-(4-fluoro-phenyl)-amine

Using a procedure similar to 1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine togive 0.053 g (yield=21%) of the title compound. MS ES not observed.

Preparation 106 C-(Tetrahydro-pyran-2-yl)-methylamine

Combine C-(Tetrahydro-pyran-2-yl)-methylamine with Sodium azide and heatto 50° C. for 15 hrs in 30 ml of DMF. Dilute the reaction withdichloromethane and wash with NaHCO₃. Treat organic layer with MgSO₄ andconcentrate. Dissolve the residue in 30 ml of ethanol with Palladium oncarbon in the presence of hydrogen gas until reaction is complete.Filter the reaction mixture. Concentrate solvent to produce 1.32 g ofthe title compound (yield=54.9%) MS ES+ 115.95.

Preparation 107 4-(3-Cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acidmethyl ester

In a 12 L RBF, charge 4-(3-iodo-indole-1-sulfonyl)-benzoic acid methylester (620 g, 1.406 mol), cyclopentene (958 g, 14.06 mol), potassiumacetate (414 g, 4.218 mol), tetrabutylammonium chloride (391 g, 1.406mol), palladium acetate (15.8 g, 0.0703 mol) and DMF (6.2 L). Heat themixture to 60° C. for sixteen hours, cool and filter through Hyflo. Washthe filter cake with ethyl acetate (5 L). Add additional ethyl acetate(4 L) and DI water (12 L). Stir for 30 minutes, separate the layers andwash the organic layer with brine (6 L). Dry the organic layer oversodium sulfate, filter and rinse the cake with ethyl acetate (2 L).Remove the solvents under vacuum to give 609 g of a dark oil. Dissolvethe oil in methylene chloride (1 L) and filter through silica gel (6kg). Wash the silica plug with MTBE (20 L) to eluent the product.Concentrate the MTBE layer under vacuum to give 535 g of an oil(yield=99.8%) of the title compound.

Preparation 108 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid methylester

In a 3 gallon autoclave, charge4-(3-Cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methyl ester (475g), ethyl acetate (2.5 L), absolute ethanol (2.5 L) and 10% Pd—C (45 g,w/w) under 35 psi hydrogen at ambient temperature for 5 hours. Filterthe crude reaction over Hyflo. Concentrate the filtrate under vacuum togive a light yellow solid (465 g) of the title compound.

Preparation 109 4-(3-Cyclo-pentyl-indole-1-sulfonyl)-benzoic acid

In a 12 L RBF, charge 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acidmethyl ester (465 g 1.213 mol) and THF (4.7 L). Add 5N NaOH (485 ml)dropwise at ambient temperature. Stir the solution at room temperatureovernight. Bring the pH of the reaction to 1 with c.HCl. Separate thelayers and extract the aqueous layer with ethyl acetate (4 L). Dry thecombined organic layers over sodium sulfate, filter and rinse with ethylacetate. Concentrate the organics under vacuum to give an off-whitesolid (401 g, yield=89.5%) of the title compound.

Preparation 110 Tetrahydro-pyran-4-carboxylic acid amide

In a 5 L flask, charge methyltetrahydropyran-4-carboxylate (500 ml, 3.75mol) and concentrated ammonium hydroxide (1.3 L) and stir the reactionat room temperature for 48 hours. Filter the reaction and dry the whitesolid in a vacuum oven at 60° C. overnight. to obtained 36.33 g whitesolid of the title compound.

Preparation 111 C-(Tetrahydro-pyran-4-yl)-methylamine

In a 2 L flask, charge tetrahydro-pyran-4-carboxylic acid amide (51 g,0.395 mol) and THF (1.3 L) and cool the reaction in an ice-bath. Add LAH(30 g, 0.791) portion-wise. Stir the reaction at 10° C. for 16 hours andquench by the drop-wise addition of DI water (30 ml), 15% NaOH (30 ml),and DI water (90 ml). Stir the reaction at ambient temperature for 16hours. Filter the salts and concentrate the filtrate under vacuum togive 36.79 g clear oil of the title compound.

Preparation 1124-{[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl}-benzoic acid

Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (1.324 mmole) withN-hydroxy-succinamide (NHS—1.457 mmoles), and EDC (1.324 mmoles) andstir in 20 ml dichloromethane for 15 hr. Condense the reaction toproduce a solid. Isolate 0.613 g (yield=97.6%). React 1.05 mmole ofresidue with 4-aminomethyl-benzoic acid (1.05 mmole) in 3 mldichloromethane for 15 hrs. Dilute reaction mixture and wash with 1 NHCl. Treat dichloromethane with MgSO₄ and concentrate. Isolate a mixtureof 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid and the title compound0.258 g (48%): MS ES+5.10-77 MS ES−509.21.

EXAMPLE 1N-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzamide

Add a 5 ml THF solution of 3-Phenyl-1H-pyrrolo[3,2-c]pyridine (500 mg,2.57 mmol, 1 eq) to a 4 ml THF solution of KotBu (303 mg, 2.70 mmol,1.05 eq) under N₂ atmosphere. Stir reaction for 10 minutes and then adda 5 ml THF solution of 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonylchloride (844 mg, 2.57 mmol, 1 eq). Stir reaction for 16 hours, removesolvent on rotovap, and purify by silica gel chromatography to giveN-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[3,2-c]pyridine-1-sulfonyl)-benzamide(982 mg, 79% yield). Mass Spectrum (m/e): 485.96 (MH+).

EXAMPLE 2N-(4-Fluoro-benzyl)-4-[3-(3-oxo-cyclopentyl)-indole-1-sulfonyl]-benzamide

Add a 3 nm DMF solution of 3-(1H-Indol-3-yl)-cyclopentanone (500 mg,2.57 mmol, 1 eq) to a 3 ml DMF solution of NaH (155 mg, 60% by weight,3.86 mmol, 1.1 eq) under N₂ atmosphere. Stir reaction for 15 minutes andthen add a 5 ml DMF solution of4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (1.27 g, 3.86mmol, 1.1 eq). Stir reaction for 48 hours, remove solvent on rotovap,and purify by silica gel chromatography to giveN-(4-Fluoro-benzyl)-4-[3-(3-oxo-cyclopentyl)-indole-1-sulfonyl]-benzamide(375 mg, 22% yield). Mass Spectrum (m/e): 490.53 (MH+).

EXAMPLE 3 N-(4-Fluoro-benzyl)-4-(3-propyl-indole-1-sulfonyl)-benzamide

Add NaH 60% in mineral oil (0.080 g, 2.0 mmol) to a stirred solution of3-propyl-indole (0.266 g, 1.67 mmol) in dr THF (25 mL) under N2. Stirthe reaction mixture at ambient temperature for 45 min. Add4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.547 g, 1.67mmol) portion wise at ambient temperature. Stir the reaction mixtureovernight at ambient temperature. Pour the reaction mixture into atwo-phase mixture of EtOAc (150 mL) and saturated solution of NaHCO₃ (50mL). Separate the organic layer, wash with brine, separate and dry(MgSO₄). Filter and evaporate the filtrate. Purify the residue on thechromatron using a 4 mm plate and eluting with a gradient hexane-EtOACsystem to give 0.262 g (34%) ofN-(4-fluoro-benzyl)-4-([3-propyl-indole-1-sulfonyl]-benzamide. Massspectrum (m/e)

M+1) 451.1.

EXAMPLE 5N-(4-Fluoro-benzyl)-4-(pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide

Add MeCN (2 ml) to a flask under N₂ containing4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (50 mg, 0.152mmol), 1H-pyrrolo[2,3-b]pyridine (18 mg, 0.152 mmol),4-Pyrrolidin-1-yl-pyridine (2 mg, 0.167 mmol), and triethylamine (17 mg,0.167 mmol). Heat reaction to 80° C. for 16 hours. Cool the solution toroom temperature, remove MeCN on rotovap. Purify crude material onsilica gel to give 45 mg (73% yield) ofN-(4-Fluoro-benzyl)-4-(pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide.Mass Spectrum (m/e): 410.1 (M+).

Prepare the following sulfonamides in Table 1 using methods similar tothe noted reference examples.

TABLE 1 Mass Spec (M + H) Ex. except where Reference No. Name Structurenoted Examples  9 N-(4-Fluoro-benzyl)-4-(indole-1-sulfonyl)-benzamide

409.0 2 10 N-(4-Fluoro-benzyl)-4-[3-spiroN-methylpiperidin-4-yl)(indole-1-sulfonyl]-benzamide

494.0 2 14N-(4-Fluoro-benzyl)-4-[3-(2-methoxy-cyclohexyl)-indole-1-sulfonyl]-benzamide

521.05 2 22N-(4-Fluoro-benzyl)-4-[3-(1-methyl-piperidin-4-yl)-indazole-1-sulfonyl]-benzamide

507.02 1 23N-(4-Fluoro-benzyl)-4-(3-phenyl-indazole-1-sulfonyl)-benzamide

485.96 1 254-(2,3-Dihydro-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

411.1 5 26 N-(4-Fluoro-benzy1)-4-(3-methyl-indole-1-sulfonyl)-benzamide

423.12 3 30 4-(3-Acetyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

451.1 3 33N-(4-Fluoro-benzyl)-4-(3-trifluoromethyl-indazole-1-sulfonyl)-benzamide

476.07(M − H) 1 344-[3-(1-Acetyl-piperidin-4-yl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide

534.03 2 35N-(4-Fluoro-benzyl)-4-[3-(4-methyl-piperazine-1-carbonyl)-indole-1-sulfonyl]-benzamide

534.94 2 36N-(4-Fluoro-benzyl)-4-[3-(1-methyl-piperidin-2-yl)-indole-1-sulfonyl]-benzamide

505.97 2 37N-(4-Fluoro-benzyl)-4-[3-(2-morpholin-4-yl-acetyl)-indole-1-sulfonyl]-benzamide

535.94 2 38N-(4-Fluoro-benzyl)-4-[3-(2-tetrahydropyran-1-acetyl)-indole-1-sulfonyl]-benzamide

506.9 2 39N-(4-Fluoro-benzyl)-4-[3-(1-methyl-piperidin-4-yl)-indole-1-sulfonyl]-benzamide

505.98 2 40N-(4-Fluoro-benzyl)-4-[3-(3,3-difluorocyclopentyl)-indole-1-sulfonyl]-benzamide

512.93 2 414-(3-Ethyl-3-methyl-2,3-dihydro-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

453.2 2dioxaneas solventAmine ref:Takayamaet al.TetrahedronLett.;1973,365, 366 42N-(4-Fluoro-benzyl)-4-(spiro[cyclopentane-1,3′-indoline])-benzamide

464.9 2dioxaneas solventJoiner, K.A.; King, F.D EuropeanPatent0287,196,1988. 43N-(4-Fluoro-benzyl)-4-(spiro[indoline-3,4′-tetrahydro-pyran])-benzamide

481.4 2dioxaneas solvent 44N-(4-Fluoro-benzyl)-4-(spiro[cyclopropane-1,3′-indoline])-benzamide

436.9 2dioxaneas solventJoiner, K.A.; King, F.D EuropeanPatent0287,196,1988. 45N-(4-Fluoro-benzyl)-4-(spiro[cyclohexane-1,3′-indoline])-benzamide

478.9 2dioxaneas solventJoiner, K.A.; King, F.D EuropeanPatent0287,196,1988. 46N-(4-Fluoro-benzyl)-4-(spiro[cyclobutane-1,3′-indoline])-benzamide

450.9 2dioxaneas solvent 47N-(4-Fluoro-benzyl)-4-(3-morpholin-4-yl-indole-1-sulfonyl)-benzamide

494 2dioxane assolvent 48N-(4-Fluoro-benzyl)-4-[3-(4-methyl-piperazin-1-yl)-indole-1-sulfonyl]-benzamide

507 2dioxane assolvent 49N-(4-Fluoro-benzyl)-4-(3-piperidin-1-yl-indole-1-sulfonyl)-benzamide

492 2dioxane assolvent 504-(3-tert-Butyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

464.97 1 51N-(4-Fluoro-benzyl)-4-[3-(1-methyl-cyclopentyl)-indole-1-sulfonyl]-benzamide

490.93 1

EXAMPLE 53N-(4-Fluoro-benzyl)-4-(3-piperidin-1-yl-indazole-1-sulfonyl)-benzamide

Dissolve 4-(3-chloro-indazole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide(91 mg, 0.20 mmol) in piperidine (11.0 mL) and stir at 90° C. overnight.Dilute the solution with EtOAc (30 mL) and wash with 1N HCl (15 mL) andsatd NaHCO₃ (15 mL). Dry, filter and concentrate the organic solutionand purify the residue by flash chromatography, using a linear gradientof 100% hexanes to 50% EtOAc/hexanes, to give the title compound as alight yellow foam (7 mg, 7%). MS (ES) 493.0 (M+1)+, 491.2 (M−1)−.

EXAMPLE 54N-(4-Fluoro-benzyl)-4-(3-morpholin-4-yl-indazole-1-sulfonyl)-benzamide

Dissolve 4-(3-chloro-indazole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide(91 mg, 0.20 mmol) in morpholine (1.0 mL) and stir at 100° C. overnight.Dilute the solution with EtOAc (30 mL) and wash with 1N HCl (11 mL),water (10 mL), and satd NaHCO₃ (10 mL). Dry, filter and concentrate theorganic solution and purify the residue by flash chromatography, using alinear gradient of 20% to 80% EtOAc/hexanes, to give the title compoundas a white foam (17 mg, 34%). MS (ES) 495.0 (M+1)+, 493.1 (M−1)−.

EXAMPLE 55N-(4-Fluoro-benzyl)-4-[3-(3-hydroxy-cyclopentyl)-indole-1-sulfonyl]-benzamide

Add sodium borohydride (23 mg, 0.601 mmol) to a 0° C. solution ofN-(4-fluoro-benzyl)-4-[3-(3-oxo-cyclopentyl)-indole-1-sulfonyl]-benzamide(295 mg, 0.601 mmol) in MeOH (7 ml) under N₂. Stir for 30 min and themwarm to room temperature. Stir for 18 hours. Add a small amount of waterto quench reaction and then remove MeOH on rotovap. Add EtOAc and waterand extract the product into organics. Separate, and dry organics overMgSO₄. Condense organics on rotovap and then purify by silica gelchromatography to giveN-(4-fluoro-benzyl)-4-[3-(3-hydroxy-cyclopentyl)-indole-1-sulfonyl]-benzamide(205 mg, 69% yield) as a light orange solid. Mass Spectrum (m/e): 493.01(MH+).

EXAMPLE 564-[3-(2,3-Dihydro-furan-3-yl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide

Add 3,4dihydrofuran (0.70 g, 0.76 mL, 0.01 mol) toN-(fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (0.534 g, 0.001mol) followed sequentially by Pd(Oac)₂ (0.024 g, 0.075 mmol), tetrabutyl ammonium chloride (0.283 g, 0013 mol), and DMF (16.0 mL). Addsodium acetate (0.246 g, 003 mol) and stir and heat the resultingmixture at 50° C. for 8 h. Pour the reaction mixture into a DMF-H₂Omixture Separate the EtOAc layer and extract it several times with H₂O.Wash with brine, dry, filter and chromatograph on the chromatron elutingwith EtOAc-hexane (3:7) to give 0.040 g of the title compound as aviscous gum. Mass spectrum (m/e) (M+1) 477; (M−1) 475.

EXAMPLE 57N-(4-Fluoro-benzyl)-4-[(3-tetrahydro-furan-3-yl)-indole-1-sulfonyl]-benzamide

Add4-[3-(2,3-dihydro-furan-3-yl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide(0.095 g, 0.10 mmol) to absolute EtOH (25 mL) and 5% P/C 0.0029 g andhydrogenate in a PARR shaker overnight at 60 lbs per square inch. Filterthe catalyst and evaporate the solvent giving 0.071 g of oil.Chromatograph on the ISCO using a gradient EtOAc-hexane system (0-100%)to give a viscous oil which solidifies to a glass 0.050 g. Mass spectrum(m/e) (M+1) 479.1441; Found (M+1) 479.1457.

EXAMPLE 60N-(4-Fluoro-benzyl)-4-(3-phenyl-2,3-dihydro-indole-1-sulfonyl)-benzamide

Add 3-phenyl-2,3-dihydro-1H-indole (Yamamoto, Y et al. Bull Chem. Soc.Jpn 44, 1971, 541-545) (0.158, 0.81 mmol),4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.266 g, 0.81mmol), Et₃N (0.161 g, 0.23 mL, 1.5 mmol) and DMAP (0.011 g, 0.09 mmol)to CH₂Cl₂ (25 mL) and stir at ambient temperature under N₂ overnight.Dilute the reaction to 150 mL with CH₂Cl₂ and pour into saturated NaHCO₃(50 mL). Separate the organic layer and extract with 1M HCl (2×75 mL).Wash with brine, separate dry (MgSO₄) filter and evaporate the filtrate.Chromatograph the residue on the ISCO using a gradient EtOAc-hexanesystem (0-100%) to give 0.167 g of the title compound. Mass spectrum(m/e) (M+1) 487.1492; Found: 487.1479.

EXAMPLE 60a Isomer 1

Separate on a chiracel column OD (0.46×255 cm) at a flow rate of 1.0mL./min, 255 nM eluting with ⅔ EtOH/heptane and 20 μL injection to give0.060 g of the desired enantiomer.

RT=5.45 min.

EXAMPLE 60b Isomer 2

Separate on a Chiracel column OD (0.46×255 cm) at a flow rate of 1.0mL./min, 255 nM, eluting with ⅔ EtOH/heptane and 20 μL injection to give0.061 g of the desired enantiomer. RT=7.20 min.

EXAMPLE 61N-(4-Fluoro-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide

Add to a 1 L 3-neck roundbottom flask previously dried overnight at 120°C. is assembled warm with an overhead stirrer, N₂ line, temperatureprobe, and dropping funnel4-(3-tetrahydro-pyran-4-yl)-indole-1-sulfonyl)-benzoic acid (15.0 g,38.94 mmol) and anhydrous THF (200 mL), stir the solution and cool to 0°C. under N₂. Add N-methylmorpholine (4.3 mL, 39.09 mmol) at once viasyringe, following by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 6.8g, 38.80 mmol) in portions as a solid. Stir the mixture for 1 h at 0° C.and treat with a solution of 4-fluorobenzylamine (4.9 mL, 42.89 mmol) inanhydrous THF (50 mL) via dropping funnel over 10 min. Warm theresulting mixture to room temperature, stir for 3 h, cool back down to0° C., and quench with 1N HCl (150 mL). Add ethyl acetate (150 mL) andseparate the layers (add a small amount of brine to more efficientlyseparate the layers). Wash the organic layer with brine (150 mL), dryover sodium sulfate, and concentrate to an oil. Dissolve the oil inmethylene chloride and add to a flash 65M biotage cartridge. Elute with3:1 hexanes/ethyl acetate followed by 3:2 hexanes/ethyl acetate toprovide isolation of the major product as a foam. Treat the foam withMTBE and re-concentrate to a paste. After standing awhile at roomtemperature, crystallization of the material occurs. Recrystallize fromethyl acetate/hexanes to provide a solid. Reslurry in MTBE (400 mL) andstir at room temperature for 3 h. longer. Filter the solid, back-washwith MTBE, dry (20 mm Hg, 55° C., to give homogeneous title compound(14.5 g, 76%); ¹H NMR (DMSO-d₆) δ 9.24 (t, J=6.0 Hz, 1H), 8.10 (m, 2H),7.98 (m, 3H), 7.67 (d, J=7.7 Hz, 1H), 7.58 (s, 1H), 7.32 (m, 5H), 7.12(t, J=8.8 Hz, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.96 (m, 2H), 3.50 (t, J=11.5Hz, 2H), 3.02 (m, 1H), 1.85 (m, 2H), 1.71 (m, 2H); MS (ESI) m/z 493(m+H); LC/MS, 100% DAD.

EXAMPLE 63(3-Aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Add trifluoroacetic acid (5 mL) to[1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-carbamicacid tert-butyl ester (853 mg, 1.56 mmol) causing much gas evolution.Rotary evaporate the reaction solution (40° C.; azeotroping 2× withMeOH). Dissolve the resultant yellow oil in MeOH (10 mL) and addhydroxide resin (Bio-Rad AG® 1-X8, 20-50 mesh; 5 g) to free-base theamine. Filter the mixture and rotary evaporate the filtrate (40° C.;azeotroped 3× with CH₂Cl₂) to yield 664 mg (95.3%) of(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneas an off-white foam. MS (m/e): 446.02 (M+1).

EXAMPLE 64 N-Azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Prepare the title compound by a similar method described for(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid tert-butyl ester (792 mg, 1.49 mmol) to give 568 mg (88.4%) ofoff-white foam. MS (m/e): 431.92 (M+1); 430.03 (M−1).

EXAMPLE 65(R)-3-Amino-pyrrolidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Prepare the title compound by a similar method described for(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing[(R)-1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-pyrrolidin-3-yl]-carbamicacid tert-butyl ester (655 mg, 1.20 mmol) to give 474 mg (88.6%) ofwhite foam. MS (m/e): 445.95 (M+1).

EXAMPLE 66((S)-3-Amino-pyrrolidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Prepare the title compound by a similar method described for(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing[(S)-1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-pyrrolidin-3-yl]-carbamicacid tert-butyl ester (903 mg, 1.65 mmol) to give 674 mg (91.4%) ofwhite foam. MS (m/e): 445.95 (M+1).

EXAMPLE 67(3-Amino-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Prepare the title compound by a similar method described for(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing[1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl]-carbamic acidtert-butyl ester (325 mg, 0.611 mmol) to give 239 mg (90.6%) of whitefoam. MS (m/e): 431.97 (M+1).

EXAMPLE 70 4-(3-Phenyl-indole-1-sulfon)-N-pyrazin-2-ylmethyl-benzamide

Add 10 ml dry DMF to a flask under N2 containing4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (500 mg, 1.33 mmol, 1.0 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (279 mg,1.46 mmol, 1.1 eq), Dimethyl-pyridin-4-yl-amine (16 mg, 0.132 mmol, 0.1eq), and C-Pyrazin-2-yl-methylamine (217 mg, 1.99 mmol, 1.5 eq). Stirfor 18 hours at room temperature. Remove solvent on rotovap and purifyby silica gel chromatography to give4-(3-Phenyl-indole-1-sulfonyl)-N-pyrazin-2-ylmethyl-benzamide (127 mg,20% yield). Mass Spectrum (m/e): 468.95 (MH+).

EXAMPLE 71N-(4-Cyano-benzyl)-4-[(3-tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide

Stir 4-(3-tetrahydro-pyran-4-yl)-indole-1-sulfonyl)-benzoic acid (0.200g, 0.518 mmole) with EDC [1892-57-5] (0.118 g, 0.662 mmoles)4-aminomethyl-benzonitrile (0.082 g, 0.662 mmoles) in dichloromethaneuntil completion. Dilute reaction and wash with 1 N HCl. Dry organiclayer over MgSO₄ and concentrate. Purify the residue via flash columnchromatography with a mixture of methanol and dichloromethane or EtOAcand dichloromethane to isolate 0.102 g of solid material (Yield=41%).Mass Spectrum (m/e): 498.04 (M−).

EXAMPLE 72(2-Phenyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (125 mg, 0.33 mmol)and 2-phenyl-azetidine (100 mg, 0.75 mmol, excess) in dichloromethane(1.0 mL) and triethylamine (0.300 mL, 2.15 mmol, excess) and addbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate(BOP Reagent) (0.150 mg, 0.33 mmol) at room temperature. Stir for 30minutes, load entire reaction directly onto pre-packed silica gel columnand purify by flash column chromatography (EtOAc/Hexanes) to yield 149mg of(2-Phenyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneas a glassy solid (92%). LRMS: MH+ 493.08.

Prepare the following sulfonamides in Table 2 using methods similar tothe noted reference examples.

TABLE 2 Mass spec Refer- (M + H) ence Ex. except where Exam- No. NameStructure Amine designated ples  734-(3-Phenyl-indole-1-sulfonyl)-N-pyrimidin-2-ylmethyl-benzamide

C-Pyrimidin-2-yl-methylamine 468.9  70  74[4-(3-Phenyl-indole-1-sulfonyl)-phenyl]-(3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-yl)-methanone

1,2,3,4,5,6-Hexahydro-[4,4′]bipyridinyl 522.1  70  754-(3-Phenyl-indole-1-sulfonyl)-N-pyridin-3-ylmethyl-benzamidehydrochloride*

Pyridin-3-yl-methylamine 467.93 72  76N-(5-Fluoro-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamideHydrochloride*

5-Fluoro-pyridin-3-yl-methylamine 485.82 72  77N-(5-Fluoro-pyridin-2-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamideHydrochloride*

5-Fluoro-pyridin-2-yl-methylamine 485.95 72  78Trans-N-(2-Hydroxy-cyclohexylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Trans-2-Aminomethyl-cyclohexanol 489.07 72  79Cis-N-(2-Hydroxy-cyclohexylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Cis-2-Aminomethyl-cyclohexanol 488.98 72  80(S)-4-(3-Phenyl-indole-1-sulfonyl)-N-(tetrahydro-furan-2-ylmethyl)-benzamide

(S)-(+)-Tetrahydro-furan-2-yl-methylamine 461.00 72  81(R)-4-(3-Phenyl-indole-1-sulfonyl)-N-(tetrahydro-furan-2-ylmethyl-benzamide

(R)-(−)-Tetrahydro-furan-2-yl-methylamine 461.01 72  824-(3-Phenyl-indole-1-sulfonyl)-N-pyridin-2-ylmethyl-benzamidehydrochloride*

Pyridin-2-yl-methylamine 467.94 72  834-(3-Phenyl-indole-1-sulfonyl)-N-pyridin-4-ylmethyl)-benzamidehydrochloride*

Pyridin-4-yl-methylamine 467.99 72  84Trans-N-(2-Hydroxy-cyclohexyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Trans-2-Amino-cyclohexanol 474.98 72  85Cis-N-(2-Hydroxy-cyclohexyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Cis-2-Amino-cyclohexanol 474.99 72  86Azetidin-1-yl[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Azetidine 416.94 72  87(4-Benzyl-piperidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

4-Benzyl-piperidine 536.05 72  88(4,4-Difluoro-piperidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

4,4-Difluoro-piperidine 480.97 72  89[4-(3-Phenyl-indole-1-sulfonyl)-phenyl]-piperidin-1-yl-methanone

Piperidine 444.97 72  90[4-(3-Phenyl-indole-1-sulfonyl)-phenyl]-pyrrolidin-1-yl-methanone

Pyrrolidine 430.96 72  914-(3-Phenyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-yl)-benzamide

Tetrahydro-pyran-4-ylamine 461.20 72  92N,N-Dimethyl-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Dimethylamine 405.10 72  931-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-piperidin-4-one

Piperidin-4-one 528.90 72  94(3-Hydroxy-piperidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

3-Hydroxy-piperidine 460.95 72  95Morpholin-4-yl-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Morpholine 446.96 72  96(2-Hydroxymethyl-piperidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Piperidin-2-yl-methanol 474.90 72  97(3-Hydroxymethyl-piperidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Piperidin-3-yl-methanol 475.00 72  98Trans-N-(4-Hydroxy-cyclohexyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Trans-4-Aminocyclohexanol 474.99 72 1004-(3-Phenyl-indole-1-sulfonyl)-N-pyridazin-3-ylmethyl-benzamide

C-Pyridazin-3-yl-methylamine 469.01 70 101N-[1-(4-Fluoro-phenyl)-piperidin-4yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide

1-(4-Fluoro-phenyl)-piperidin-4-ylamine 552.38(M⁻) 70 1024-(3-Phenyl-indole-1-sulfonyl)-N-(1-phenyl-piperidin-4-ylmethyl)-benzamide

C-(1-Phenyl-piperidin-4-yl)-methylammine 550.06 70 103(R)-N-[1-(4-Fluoro-phenyl)-pyrrolidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide

(R)-1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine 539.97 70 104(S)-N-[1-(4-Fluoro-phenyl)-pyrrolidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl-benzamide

(S)-1-(4-Fluoro-phenyl)-pyrrolidin-3-ylammine 540.00 70 105N-[1-(4-Fluoro-phenyl)-azetidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide

1-(4-Fluoro-phenyl)-azetidin-3-ylamine 525.96 72 1064-(3-Phenyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

4-aminomethyltetrahydropyran 475.0  72 107N-(2-Methoxy-ethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

2-methoxyethylamine 434.96 72 108N-(2-Isopropoxy-ethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

2-aminoethyl-propylamine 462.99 72 109N-(2-Ethoxy-ethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

2-ethoxyethyl-amine 434.96 72 1104-[[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl]-benzoicacidmethyl ester

4-aminomethyl-benzoic acidmethyl ester 525.07 72 111N-(3-Methoxy-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-ethyl-benzamide

3-methoxybenzylamine 496.93 72 112N-(4-Dimethylamino-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

4-dimethylamino-benzylamine 510.01 72 113N-(4-amino-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

4-aminobenzylamine 481.94 72 114(2-Phenylaminomethyl-pyrrolidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

(4-Fluoro-phenyl)-pyrrolidin-3-ylmethyl-amine 536.03 70 1152-[1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-isoindole-1,3-dione

2-Azetidin-3-ylmethyl-isoindole-1,3-dione 576.02 70 1163-[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacidtert-butyl ester

3-Amino-azetidine-1-carboxylic acidtert-butyl ester 531.95 70 117(R)-1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-pyrrolidin-3-yl]-carbamicacid tert-butyl ester

(R)-Pyrrolidin-3-yl-carbamic acidtert-butyl ester 546.05 70 118[(S)-1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-pyrrolidin-3-yl]-carbamicacid tert-butyl ester

(S)-Pyrrolidin-3-yl-carbamic acidtert-butyl ester 546.01 70 119[1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-carbamicacid tert-butyl ester

Azetidin-3-ylmethyl-carbamic acidtert-butyl ester 546.17 70 120[1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl]-carbamicaacidtert-butyl ester

Azetidin-3-yl-carbamic acidtert-butyl ester 532.02 70 121N-Cyclobutyl-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Cyclobutyl amine 430.98 70 1223-[[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl]-azetidine-1-carboxylicacidmethyl ester

3-Aminomethyl-azetidine-1-carboxylic acidmethyl ester 503.98 70 123(3-Hydroxymethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Azetidin-3-yl-methanol 447.2  72 124N-(Tetrahydro-(R)-furan-2-ylmethyl)-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide

(R)(−)(Tetrahydro-furan-2-yl)-methanol 468.9  72 126N-(2-Methoxy-cyclohexyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

2-Methoxy-cyclohexylamine 489.05 70 127N-[1-(4-Fluoro-phenyl)-pyrrolidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide

1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine 540.2  70 1283-[-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-pyrrolidine-1-carboxylicacidmethyl ester

3-Amino-pyrrolidin-1-carboxylic acidmethyl ester 504.02 70 129[4-(3-Fluoro-phenyl)-piperidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

4-(3-Fluoro-phenyl)piperidine 539.09 70 1304-[3-(2-Fluoro-pyridin-3-yl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

4-aminomethyltetrahydropyran 494.01 70 131N-Cyclobutyl-4-[3-(2-fluoro-pyridin-3-yl)indole-1-sulfonyl]-benzamide

Cyclobutyl amine 449.99 70 132N-Cyclopropyl-methyl-4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzamide

Cyclopropylmethyl amine 449.94 70 1334-[3-(6-Fluoro-pyridin-3-yl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

4-aminomethyltetrahydropyran 493.90 70 134N-Cyclopropylmethyl-4-[3-(6-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzamide

Cyclopropylmethyl amine 449.94 70 1354-(3-Cyclopentyl-indole-1-sulfonyl)-N-cyclopropylmethyl-benzamide

Cyclopropylmethyl amine 422.99 70 1364-(3-Cyclopentyl-indole-1-sulfonyl)-N-cyclopropylmethyl-benzamide

Cyclopropylmethylamine 423.00 72 1374-(3-Cyclopentyl-indole-1-sulfonyl)-N-cyclobutyl-benzamide

Cyclopropylamine 423.00 70 138Azetidin-1-yl-[4-(3-cyclopentyl-indole-1-sulfonyl)-phenyl]-methanone

azetidine 409.02 70 139N-(5-Cyano-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

5-Aminomethyl-nicotinonitrile 492.91 70 1404-(3-Cyclopentyl-indole-1-sulfonyl)-N-[(R)-1-(tetrahydro-furan-2-yl)methyl]-benzamide

R-(Tetrahydro-furan-2-yl)-methylamine 452.96 70 141N-Cyclopropylmethyl-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide

Cyclopropylmethyl amine 438.93 72 1424-(3-Phenyl-indole-1-sulfonyl)-N-(tetrahydro-ffuran-3-ylmethyl)-benzamide

C-(Tetrahydro-furqan-3-yl)-methylamine 460.96 72 143N-(4-Cyano-benzyl)-4-[3-(cyclopentyl)-indole-1-sulfonyl]-benzamide

4-Aminomethyl-benzonitrile 498.04 72 144N-(4-Cyano-benzyl)-4-(3-cyclopropyl-indole-1-sulfonyl)-benzamide

4-Aminomethyl-benzonitrile 455.92 70 1454-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-2-ylmethyl)-benzamide

C-(Tetrahydro-pyran-2-yl)-methylamine 473.11(M + 1)− 72 146N-(4-Amino-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

4-Aminomethyl-benzonitrile 482.07(M + 1)− 72 147N-Isobutyl-4-(3-phenyl-indole-1-sulfonyl)-benzamide

isobutylamine  433.1598 70 148N-Isoamyl-4-(3-phenyl-indole-1-sulfonyl)-benzamide

isoamylamine  447.1752 70 149N-2-methylbutylamine-4-(3-phenyl-indole-1-sulfonyl)-benzamide

2-methylbutlyamine  447.1738 72 1504-(3-Cyclopropyl-indole-1-sulfonyl)-N-(5-fluoro-pyridin-2-ylmethyl)-benzamide

C-(5-Fluoro-pyridin-2-yl)-methylamine 450   70 1514-(3-Cyclopropyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

4-aminomethyltetrahydropyran 439.1  70 1524-(3-Cyclopropyl-indole-1-sulfonyl)-N-(2-ispropoxy-ethyl)-benzamide

2-Isopropoxy-ethylamine 427   70 153N-(4-Cyano-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

4-Aminomethyl-benzonitrile 491.94 72 154N-(5-Fluoro-pyridin-2-ylmethyl)-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide

C-(5-Fluoro-pyridin-2-yl)-methylamine 493.89 72 1554-[3-(Tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

4-aminimethyltetrahydropyran 482.93 72 156N-Cyclobutyl-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide

Cyclobutyl amine 438.98 72 157N-(5-Fluoro-pyridin-3-ylmethyl)-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide

C-(5-Fluoro-pyridin-3-yl)-methylamine 493.95 72 157aN-Cyclopropylmethyl-4-(3-phenyl-indole-1-sulfonyl)-benzamide

cyclopropylmethyl amine 431.2  72 157b4-(3-Cyclopentyl-indole-1-sulfonyl)-N-pyridin-3-ylmethyl-benzamide

Pyridin-3-yl-methylamine M − 1458   72 157c4-(3-Cyclopentyl-indole-1-sulfonyl)-N-piperidin-1-yl-benzamide

N-aminopiperidine 452.1  72 157d4-(3-Phenyl-indole-1-sulfonyl)-N-piperidin-1-yl-benzamide

N-aminopiperidine 460.1  72 *Dissolve the purified compound in a minimumamount of tetrahydrofuran, cool to 0° C. and treat wwith 1-2 equivalentsof anhydrous HCl in THF and evaporate the solvents to give the final HClsalt.

EXAMPLE 158 Resolution ofCis-N-(2-Hydroxy-cyclohexyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Separate the title compound by chiral chromatography (prep ChiralPak AD,100% EtOH, 14 mL/min, analytical ChiralPak AD, 100% EtOH, 1.0 mL/min.Isomer 1 retention time (analytical) 8.35 min LRMS: 475.06. Isomer 2retention time (analytical) 11.85 min LRMS: 475.05.

EXAMPLE 159 Resolution ofTrans-N-(2-Hydroxy-cyclohexylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Separate the title compounds by chiral chromatography (prep ChiralPakAD, 100% EtOH, 14 mL/min, analytical ChiralPak AD, 100% EtOH, 1.0mL/min. Isomer 1 retention time (analytical) 6.75 min LRMS: 489.10.Isomer 2 retention time (analytical) 9.55 min LRMS: 489.11.

EXAMPLE 161(3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Dissolve 1-Benzhydryl-azetidin-3-ol (250 mg, 1.04 mmoL) in methanol (3.0mL) and add to Pd(OH)₂ (50 mg) under nitrogen. Degas reaction vessel andpurge with 60 psi H2 (g). Repeat degass/H₂ purge cycle again. Allow tostir under 60 psi H₂ for 15 h. Release reaction and filter throughcelite with additional methanol. Evaporate methanol to yieldazetidin-3-ol as a liquid which is used without further purification.Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.53 mmol)and azetidin-3-ol (50 mg, 0.68 mmol, excess) in dichloromethane (1.0 mL)and triethylamine (0.500 mL, 3.58 mmol, excess) and addbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate(BOP Reagent) (300 mg, 0.66 mmol, excess) at room temperature. Stir for30 minutes, load entire reaction directly onto pre-packed silica gelcolumn and purify by flash column chromatography (EtOAc/Hexanes) toyield 167 mg of(3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneas a white foam (73%). LRMS: MH+ 432.97.

EXAMPLE 162 Methanesulfonic acid1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl ester

Prepare the title compound utilizing Methanesulfonic acid1-benzhydryl-azetidin-3-yl ester in the same procedure as above.

EXAMPLE 163 Dimethyl-carbamic acid1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl ester

Combine(3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(95 mg, 0.219 mmol), triethylamine (0.200 mL, 1.43 mmol, excess) and4-dimethylaminopyridine (5 mg, 0.04 mmol) in dichloromethane (1.0 mL)and treat with N,N-dimethylcarbamoyl chloride (0.050 mL) at roomtemperature. Stir for 15 h, load directly onto pre-packed silica gelcolumn and purify by flash column chromatography (EtOAc/Hexanes) toyield 82 mg of Dimethyl-carbamic acid1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl ester as awhite foam (74%). LRMS: MH+ 503.97.

EXAMPLE 164N-[1-(4-Fluoro-phenyl)-azetidin-3-ylmethyl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Add trifluoroacetic acid (2 mL) to[1-(4-fluoro-phenyl)-azetidin-3-ylmethyl]-carbamic acid tert-butyl ester(135 mg, 0.482 mmol) causing much gas evolution. Rotary evaporate thereaction solution (40° C.; azeotroping 3× with CH₂Cl₂). Dissolve thismaterial in anhydr CH₂Cl₂ (3 mL). Add4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.53 mmol, 1.1equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC; 140 mg, 0.73 mmol, 1.5 equiv), and 4-(dimethylamino)pyridine(DMAP; 270 mg, 2.3 mmol, 4.7 equiv). After stirring 16 h, transfer thereaction solution to a column of silica gel (80 mm×20 mm dia.) and elute(10-45% EtOAc/hex) to yield 31 mg (12%) ofN-[1-(4-fluoro-phenyl)-azetidin-3-ylmethyl]-4-(3-phenyl-indole-1-sulfonyl)-benzamideas a light-yellow foam. MS (m/e): 539.99 (M+1); 538.16 (M−1).

EXAMPLE 165[3-[(4-Fluoro-phenylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Add 1-bromo-4-fluorobenzene (220 μL, 350 mg, 2.0 mmol, 2.0 equiv) to amixture of(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(446 mg, 1.00 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium(0)(23 mg, 0.025 mmol, 0.025 equiv), 2-(di-tert-butylphosphino)biphenyl (15mg, 0.057 mmol, 0.050 equiv), and sodium tert-butoxide (120 mg, 1.2mmol, 1.2 equiv) in anhydr toluene (4 mL) and heat at 100° C. for 19 h.After cooling, transfer the reaction mixture through a 0.45-μm filterdisc to a column of silica gel (125 mm×25 mm dia.) and elute (10-100%EtOAc/hex) to yield 98 mg (18%) of[3-[(4-fluoro-phenylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneas a light-yellow foam. ¹H NMR indicated pure desired product. MS (m/e):540.07 (M+1); 538.19 (M−1).

EXAMPLE 166[(R)-3-(4-Fluoro-phenylamino)-pyrrolidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Prepare the title compound by a similar method described for[3-[(4-Fluoro-phenylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing((R)-3-Amino-pyrrolidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(334 mg, 0.750 mmol) to isolate 35 mg (8.7%) of light-yellow foam. MS(m/e): 540.01

EXAMPLE 167[(S)-3-(4-Fluoro-phenylamino)-pyrrolidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Prepare the title compound by a similar method described for[3-[(4-Fluoro-phenylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1sulfonyl)-phenyl]-methanone using((S)-3-Amino-pyrrolidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(334 mg, 0.750 mmol) to isolate 59 mg (15%) of light-yellow foam. MS(m/e): 540.02 (M+1).

EXAMPLE 170[3-[(6-Fluoro-pyridin-2-ylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Add 2,6-difluoropyridine (55 μL, 70 mg, 0.61 mmol, 2.0 equiv) to asolution of(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(134 mg, 0.301 mmol, 1 equiv) and triethylamine (120 μL, 87 mg, 0.86mmol, 2.9 equiv) in 1,4-dioxane (3 mL) and heat at 80° C. for 16 h. Massspec shows no desired product. Add more triethylamine (120 μL) and2,6-difluoropyridine (110 μL). After 32 h at 80° C., LC/MS shows a smallamount of desired product. Add more triethylamine (200 μL) and2,6-difluoropyridine (110 μL). After 38 h, add more triethylamine (200μL) and 2,6-difluoropyridine (110 μL). After 100 h, transfer thereaction solution to a column of silica gel (80 mm×20 mm dia.) and elute(50-65% EtOAc/hex) to yield 65 mg (40%) of[3-[(6-fluoro-pyridin-2-ylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneas a white foam. MS (m/e): 541.02 (M+1); 539.17 (M−1).

EXAMPLE 171[4-(3-Phenyl-indole-1-sulfonyl)-phenyl]-[3-(pyrimidin-2-ylaminomethyl)-azetidin-1-yl]-methanone

Prepared the title compound by a similar method as described for[3-[(6-Fluoro-pyridin-2-ylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneusing(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(134 mg, 0.301 mmol) to isolate 56 mg (36%) of off-white foam. MS (m/e):524.01 (M+1).

EXAMPLE 1721,1-Dimethyl-3-[1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-urea

and EXAMPLE 1731,1-Dimethyl-3-[1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-thiourea

Add dimethylthiocarbamoyl chloride (350 mg, 2.8 mmol, 12 equiv) to asuspension of(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(101 mg, 0.227 mmol, 1 equiv) and triethylamine (130 μL, 94 mg, 0.93mmol, 4.1 equiv) in anhydr CH₂Cl₂ (3 mL). After stirring 17 h, transferthe reaction to a column of silica gel (80 mm×20 mm dia.) and elute(20-100% EtOAc/hex; 2% MeOH/CH₂Cl₂) to yield 15 mg (12%) of1,1-dimethyl-3-[1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-ureaas a white foam. The starting dimethylthiocarbamoyl chloride containssome dimethylcarbamoyl chloride.

Elute the column of silica gel with more polar solvent (20% MeOH/CH₂Cl₂)to give the thiourea along with triethylamine hydrochloride. Dissolvethis material in CH₂Cl₂ and wash with satd aq NaHCO₃. Dry the organiclayer (anhydr MgSO₄) and rotary evaporate (40° C.) to yield 30 mg (25%)of1,1-dimethyl-3-[1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-ylmethyl]-thioureaas a tan foam.

EXAMPLE 1743-[(4-Fluoro-benzylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone

Add 4-fluorobenzaldehyde (26 μL, 31 mg, 0.25 mmol, 1.0 equiv) to asolution of(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(112 mg, 0.251 mmol, 1 equiv) in MeOH (1 mL). After a few minutes,observe white precipitate. After 1 h, add H₂O and extract the reactionmixture with CHCl₃ (3×). Combine the organic layers, dry and rotaryevaporate (40° C.) to give 120 mg of imine as a colorless film. Dissolvethe imine anhydr THF (2 mL) and add sodium triacetoxyborohydride (80 mg,0.38 mmol, 1.5 equiv). After 19 h, quench the reaction mixture with satdaq NaHCO₃ (5 mL) and extract with EtOAc (5 mL). Dry the organic layer(anhydr MgSO₄) and rotary evaporate (40° C.). Transfer the resultantcolorless oil to a column of silica gel (60 mm×12 mm dia.) and elute (2%MeOH/CH₂Cl₂) to yield 54 mg (39%) of[3-[(4-fluoro-benzylamino)-methyl]-azetidin-1-yl]-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneas a white foam. MS (m/e): 553.96 (M+1).

EXAMPLE 175N-[1-(4-Fluoro-phenyl)-azetidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Add 1-bromo-4-fluorobenzene (110 μL, 180 mg, 1.0 mmol, 2.0 equiv) to amixture of N-azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide (216mg, 0.501 mmol, 1 equiv), tris(dibenzylideneacetone)dipalladium(0) (12mg, 0.012 mmol, 0.025 equiv), 2-(di-tert-butylphosphino)biphenyl (8 mg,0.03 mmol, 0.05 equiv), and sodium tert-butoxide (58 mg, 0.60 mmol, 1.2equiv) in anhydr toluene (2 mL). Heat the reaction mixture at 100° C.for 14 h. After cooling, dilute the reaction mixture with CH₂Cl₂ andtransfer through a 0.45-μm filter disc to a column of silica gel (80mm×20 mm dia.) and elute (10-35% EtOAc/hex) to yield 63 mg (24%) ofN-[1-(4-fluoro-phenyl)-azetidin-3-yl]-4-(3-phenyl-indole-1-sulfonyl)-benzamideas a white solid.

EXAMPLE 1763-[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid methyl ester

Add methyl chloroformate (60 μL, 73 mg, 0.78 mmol, 3.1 equiv) to asuspension of N-azetidin-3-yl-4-(3-phenyl-indole-1-sulfonyl)-benzamide(108 mg, 0.250 mmol, 1 equiv) and triethylamine (140 μL, 100 mg, 1.0mmol, 4.0 equiv) in anhydr (CH₂Cl₂ (3 mL). Observe a vigorous gasevolution. After stirring 4 h, rotary evaporate the reaction solution.Transfer the resultant material to a column of silica gel (80 mm×20 mmdia.) and elute (20-60% EtOAc/hex) to yield 84 mg (69%) of3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid methyl ester as an off-white foam. MS (m/e): 489.96 (M+1); 488.09(M−1).

EXAMPLE 177[(R)-1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-pyrrolidin-3-yl]-carbamicacid methyl ester

Prepare the title compound by a similar method described for3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid methyl ester using((R)-3-amino-pyrrolidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(111 mg, 0.249 mmol) to isolate 98 mg (78%) of white foam. MS (m/e):503.98 (M+1); 502.09 (M−1).

EXAMPLE 178[(S)-1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-pyrrolidin-3-yl]-carbamicacid methyl ester

Prepare the title compound by a similar method described for3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid methyl ester using((S)-3-amino-pyrrolidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(111 mg, 0.249 mmol) to isolate 97 mg (77%) of white foam. MS (m/e):504.00 (M+1); 502.09 (M−1).

EXAMPLE 179[1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl-methyl]-carbamicacid methyl ester

Prepare the title compound by a similar method described for3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid methyl ester using(3-aminomethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(111 mg, 0.249 mmol) to isolate 99 mg (79%) of white foam. MS (m/e):504.02 (M+1); 502.15 (M−1).

EXAMPLE 180[1-[4-(3-Phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl]-carbamic acidmethyl ester

Prepare the title compound by a similar method described for3-[4-(3-phenyl-indole-1-sulfonyl)-benzoylamino]-azetidine-1-carboxylicacid methyl ester using(3-amino-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone(111 mg, 0.249 mmol) to isolate 99 mg (79%) of white foam. MS (m/e):489.99 (M+1): 488.04 (M−1).

EXAMPLE 183N-(4-Fluoro-benzyl)-4-(3-pyridin-3-yl-indole-1-sulfonyl)-benzamidehydrochloride

Combine N-(4-fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide 300mg, 0.56 mmol, 1 equiv), 3-tributylstannylpyridine (FrontierScientific®; 90%; 230 mg (0.90)=210 mg, 0.56 mmol, 1.0 equiv), andtetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol, 0.15equiv) in deoxygenated toluene (3 mL) and heat at 100° C. for 18 h.Transfer the reaction solution to a column of silica gel (125 mm×25 mmdia.) and elute (0-70% EtOAc/hex) to yield 73 mg (27%) of free amine asan orange oil. Dissolve this material in MeOH (5 mL) and add 12 M aq HCl(2 drops). Rotary evaporate this solution (40° C.) to yield 78 mg (27%)of N-(4-fluoro-benzyl)-4-(3-pyridin-3-yl-indole-1-sulfonyl)-benzamidehydrochloride as a brown glass. MS (m/e): 485.95 (M+1); 484.10 (M−1).

EXAMPLE 184N-(4-Fluoro-benzyl)-4-(3-pyridin-2-yl-indole-1-sulfonyl)-benzamidehydrochloride

Prepare the title compound by a method similar to Example 183 using2-tributylstannylpyridine (Frontier Scientific®; 85%; 250 mg [0.85]=210mg, 0.58 mmol, 1.0 equiv) to isolate 109 mg (37%) of yellow glass. MS(m/e): 485.96 (M+1); 484.10 (M−1).

EXAMPLE 185N-(4-Fluoro-benzyl)-4-[3-(6-methoxy-pyridin-3-yl)-indole-1-sulfonyl]-benzamide

CombineN-(4-Fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboralan-2-yl)-indole-1-sulfonyl]-benzamide(0.534 g, 1.0 mmol), 5-Bromo-2-methoxy pyridine (0.155 mL, 1.2 mmol) andPdCl₂(dppf).CH₂Cl₂ (0.088 g, 0.07 mmol) in dry DMF (40 mL). Add 2MNa₂CO₃ (1.40 mL, 2.8 mmol) and heat under N₂ at 100° C. for 4 h. Stirovernight at ambient temperature. Pour the reaction mixture intoEtOAc-H₂O, separate, extract several times with H₂O and wash with brine.Dry the EtOAc (MgSO₄) and filter through Celite®. Evaporate andchromatograph using a hexane-EtOAc gradient 0-100% EtOAc to give 0.347 g(67%) of the desired compound. MS (M+1) 516; (M−1) 514.

EXAMPLE 186N-(4-Fluoro-benzyl)-4-[3-(6-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzamide

CombineN-(4-Fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-sulfonyl]-benzamide(150 mg, 0.28 mmol), 5-Bromo-2-fluoro-pyridine (0.05 mL, 0.56 mmol), CsF(212 mg, 1.4 mmol) and Pd(Ph₃P)₄ (32 mg, 0.028 mmol) in 1.0 mL DMF and0.100 mL of water. Evacuate the reaction vessel and place under anatmosphere of nitrogen. Heat the resulting reaction at 90 degrees 12 h.Load the reaction directly onto silica gel and purify by flash columnchromatography (EtOAc/Hexanes) to yield 98 mg of white foam (70%) LRMS:MH+ 504.02.

EXAMPLE 1874-[3-(5-Chloro-thiophen-2-yl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide

CombineN-(4-Fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboralan-2-yl)-indole-1-sulfonyl]-benzamide(0.534 g, 1.0 mmol), 2-bromo-5-chloro-thiophene (0.012 mL, 1.1 mmol),PdCl₂(dppf), CH₂Cl₂ (0.051 g, 0.069 mmol) and KOAc (0.294 g, 3.0 mmol)in dry DMF (22.0 mL) under N₂ heat and stir at 100° C. for 16 h. Cool toambient temperature and pour into a mixture of EtOAc-H₂O. Separate andextract the EtOAc several times with H₂O, wash with brine and dry(MgSO₄). Filter and evaporate to an oily residue. Purify the product bychromatography using a hexane-EtOAc gradient 0-100% EtOAc to give 0.209g (40%) of a viscous oil. TOF MS (M−1) 523.0332.

EXAMPLE 1884-(3-Cyclopropropyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

Combine N-(4-fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (0.50g, 0.94 mmol), cyclopropylboronic acid (0.24 g, 2.8 mmol),tricyclohexylphosphine (0.05 g, 0.18 mmol), potassium phosphate (0.70 g,3.30 mmol), and palladium acetate (0.02 g, 0.09 mmol) in a mixture oftoluene (15 mL) and water (0.4 mL). Heat to 100° C. under nitrogen for18 hours, filter through celite, and wash solids with EtOAc. Wash EtOAcwith saturated NaHCO₃ (30 mL), then dry with Na₂SO₄, and concentrateunder vacuum. Purify by flash column on silica gel eluting with 0-50%EtOAc in hexanes to give the title compound (0.25 g, 60%). MS (ES) 449.2(M+1)+, 447.4 (M−1)−.

EXAMPLE 189N-(4-Fluoro-benzyl)-4-(3-thiophen-3-yl-indole-1-sulfonyl)-benzamide

Combine N-(Fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (0.534g, 1.1 mmol), thiophene-3-boronic acid (0.154 g, 1.25 mmol),PdCl₂(dppf).CH₂Cl₂ (0.10 mmol) and 2 M Na₂CO₃ (1.32 mL)l, 2.64 mmol)respectively in dry DMF (40 mL) under N₂. Stir and heat at 81° C. underN₂ for one and a half hours. Cool to ambient temperature and stirovernight. Pour the reaction into EtOAc (150 mL) and extract with H₂O(3×150 mL). Wash with brine, separate and dry the organic layer (MgSO₄).Filter through celite and evaporate the filtrate on the rotaryevaporator. Chromatograph using a hexane-EtOAc gradient from 0-100%EtOAc to give 0.352 g (71%) of the desired compound as and off whitesolid MS (ES+) (M+1) 491.0; (M−1) 490.10.

EXAMPLE 1904-[3-(2-Chloro-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide

Add N-(4-Fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (268 mg,0.0.50 mmol), 2-chlorophenylboronic acid (78.2 mg, 0.50 mmol),PdCl₂(dppf).CH₂Cl₂ (41 mg, 0.05 mmol) and 2M Na₂CO₃ (0.55 mL, 1.1 mmol)respectively to DMF (15.0 mL) at ambient temperature under N₂. Heat thereaction to 100° C. for 16 h. Cool the reaction to ambient temperatureand pour into a H₂O-EtOAc mixture (200 mL/100 mL). Separate the EtOAc,extract several times with H₂O and wash with brine. Dry (MgSO₄), filterand evaporate the filtrate. Purify the crude material on silica gelusing a gradient hexane-EtOAc system to give 0.155 g (60% yield) of4-[3-(2-chloro-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide:Mass spectrum (m/e)

M−1) 517.0787.

EXAMPLE 191N-(4-Fluoro-benzyl)-4-[3-(2-fluoro-pyridin-3-yl)-indole-1-sulfonyl]-benzamide

Combine N-(4-Fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide (300mg, 0.56 mmol), 2-Fluoro-3-boronic acid-pyridine (140 mg, 1.12 mmol),CsF (170 mg, 1.12 mmol) and Dichlorobis(triphenylphosphine)palladium(100 mg, 0.14 mmol) in dioxane (2.0 mL) and water (0.200 mL). Evacuatethe reaction and place under a nitrogen atmosphere. Heat the resultingreaction in an 80 degree oil bath for 15 h. Cool the reaction and filterthrough a short pad of silica gel with additional ethyl acetate.Evaporate and purify by flash column chromatography (EtOAc/Hexanes) toyield 141 mg of an off white foam (50%) LRMS: MH+ 503.92.

Prepare the following sulfonamides in Table 3 using methods similar tothe noted reference examples.

TABLE 3 Ex. MS data (m/e) Reference No. Final Structure Name (M + H)Examples 194

N-(4-Fluoro-benzyl)-4-(3-pyridin-4-yl-indole-1-sulfonyl)-benzamide486.13 189 195

N-(4-Fluoro-benzyl)-4-(3-thiophen-2-yl-indole-1-sulfonyl)-benzamide512.73 189 196

N-(4-Fluoro-benzyl)-4-[3-(2-fluoro-phenyl)-indole-1-sulfonyl]-benzamide503.12 189 197

N-(4-Fluoro-benzyl)-4-[3-(3-fluoro-phenyl)-indole-1-sulfonyl]-benzamide501.2  190 198

N-(4-Fluoro-benzyl)-4-[3-(4-fluoro-phenyl)-indole-1-sulfonyl]-benzamide503.1  189 199

N-(4-Fluoro-benzyl)-4-(3-furan-3-yl-indole-1-sulfonyl)-benzamide 475.11189 200

N-(4-Fluoro-benzyl)-4-(3-o-tolyl-indole-1-sulfonyl)-benzamide 499.1  189201

4-[3-(4-Chloro-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide517.08 189 202

4-[3-(3-Chloro-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide437.13 189 203

N-(4-Fluoro-benzyl)-4-(3-isoquinolin-4-yl-indole-1-sulfonyl)-benzamide534.13 185 205

N-(4-Fluoro-benzyl)-4-(3-m-tolyl-indole-1-sulfonyl)-benzamide 499.15 187206

N-(4-Fluoro-benzyl)-4-[3-(3-methoxy-phenyl)-indole-1-sulfonyl]-benzamide515.14 187 208

N-(4-Fluoro-benzyl)-4-(3-furan-2-yl-indole-1-sulfonyl)-benzamide 475.11189 209

N-(4-fluoro-benzyl)-4-[3-(5-methyl-thiophene-2-yl)-indole-1-sulfonyl]-benzamide505.1  189 210

N-(4-fluorobenzyl)-4-(3-p-tolyl-indole-1-sulfonyl)-benzamide 499.15 185211

N-(4-Fluoro-benzyl)-4-(3-quinolin-6-yl-indole-1-sulfonyl)-benzamide536.14 185 212

4-[3-(4-Dimethylamino-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamidehydrochloride*550   185 213

N-(4-Fluoro-benzyl)-4-[3-(3-fluoro-pyridin-4-yl)-indol-1-sulfonyl]-benzamideMH+503.96 186 *Dissolve the purified compound in minimum amount oftetrahydrofuran, cool to 0° C. and treat with 1-2 equivalents ofanhydrous HCl in THF, evaporate the solvents to give the final HCl salt.

EXAMPLE 214N-(4-Fluoro-benzyl)-4-(3-pyrimidin-2-yl-indole-1-sulfonyl)-benzamide

Stir a mixture ofN-(4-fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaboralan-2-yl)-indole-1-sulfonyl]-benzamide(0.200 g, 0.374 mmoles), 2-bromo-pyrimidine (0.282 g, 1.872 mmole),Tetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.0374 mmoles),Cesium Fluoride (0.282 g, 1.872 mmole) in dioxane until reaction goes tocompletion at 90° C. Concentrate the reaction and purify via columnchromatography using a mixture of EtOAc and Hexanes to give 0.049 g ofsolid material (yield=27%): Mass Spectrum (m/e): 485.09 (M⁻).

EXAMPLE 215N-(4-Fluoro-benzyl)-4-(3-pyrimidin-5-yl-indole-1-sulfonyl)-benzamide

Prepare the title compound by a similar method ofN-(4-Fluoro-benzyl)-4-(3-pyrimidin-2-yl-indole-1-sulfonyl)-benzamideusing 5-bromo-pyrimidine (0.118 g, 0.748 mmoles) to isolate 0.070 g ofsolid (yield=95%). Mass Spectrum (m/e): 486.1 (M⁺).

EXAMPLE 216N-(4-Fluoro-benzyl)-4-(3-pyrimidin-5-yl-indole-1-sulfonyl)-benzamide:chloride

StirN-(4-Fluoro-benzyl)-4-(3-pyrimidin-5-yl-indole-1-sulfonyl)-benzamide(0.041 g, 0.084 mmole) in dioxane with 1 N HCl until completion andremove solvent to isolate 0.026 g (Yield=61%).

EXAMPLE 217N-(4-Fluoro-benzyl)-4-(3-pyrazin-2-yl-indole-1-sulfonyl)-benzamide

Degas DMF with N₂ for 30 minutes. Add 2-tributylstannyl pyrazine (0.214g, 0.58 mmol),N-(4-fluoro-benzyl)-4-(3-iodo-indole-1-sulfonyl)-benzamide 0.300 g, 0.56mmol) and tetrakis(triphenylphosphine)Pd(0) (0.100 g, 0.086 mmol) to DMF(5.0 ml). Heat and stir at 100° under N₂ for 16 h. Pour the reactionmixture into H₂O-EtOAc. Separate the EtOAc layer and extract severaltimes with H₂O, wash with brine, dry (MgSO₄) and filter through celite.Remove the solvent on the rotary evaporator to give an oil.Chromatograph on the chromatron using a 1 mm plate and elute with 1%CH₃OH—CH₂Cl₂ to give the title compound. Mass spectrum (m/e) (M+H)487.1240; found: 487.1220.

EXAMPLE 218 N-(4-Fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

In a 100 ml RBF combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (2.5g, 6.62 mmol) and THF (25 ml). Cool the solution in an ice water bathand add 4-methylmorpholine (0.73 ml, 7.29 mmol) follow by the portionwise addition of CDMT (1.16 g, 7.29 mmol). Stir the solution in an icewater bath for one hour. Add dropwise, a solution of 4-fluorobenzylamine(0.83 ml, 7.29 mmol) in THF (8 μl) to the reaction at 0° C. Stir thesolution at 0° C. for five hours, and quench with 1N HCl (50 ml).Extract the reaction MTBE (2×50 ml), filter and wash with saturatedaqueous sodium chloride (50 ml). Dry the organics over magnesiumsulfate, filter and concentrate to giveN-(4-fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide (2.43 g) asa white solid. HPLC=95.5%, MS (ESI) m/z observed 485.1334 calculated485.1335 (M+H).

Dissolve 4 g ofN-(4-fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide in 15 mL ofabsolute ethanol. As the sample wetted, sonicate and observecrystallization. Collect a powder diffraction pattern on these crystals.Characterize the crystals as having a melt onset beginning at 140° C.

EXAMPLE 2194-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-yl)-benzamide

Stir a solution of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid(19.0 g, 51.43 mmol) in anhydrous THF (250 mL), cool to 5° C., addN-methylmorpholine (5.8 mL, 52.72 mmol) and2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). Stirthe mixture at 0-5° C. for 1 h, add a solution of4-aminotetrahydro-pyran (5.8 g, 57.36 mmol) in dry THF (75 mL) viadropping funnel. Bring the mixture to room temperature, stir for 3 h,and cool back down to 5° C. Stir the mixture and add 1N HCl (250 mL),add the resulting solution to a separatory funnel, and extract withethyl acetate (250 mL). Separate the layers, wash the organic layer withbrine (250 mL), and combine the aqueous layers and extract with ethylacetate (250 mL). Combine the organics and wash with saturated aqueoussodium bicarbonate (400 mL) and dry the organic layer over sodiumsulfate. Concentrate to give a foam, dissolve in minimum methylenechloride, and add to a biotage flash 65M cartridge. Elute with 3:2hexanes/ethyl acetate to provide the major product as a foam, and dry(20 mm Hg, 40° C.) to give a white powder of pure product (20.3 g, 87%);MS (ESI) m/z 453 (m+H).

EXAMPLE 2204-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

Stir a stir solution of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid(19.0 g, 51.43 mmol) in anhydrous THF (250 mL) cool to 5° C. under N₂add N-methylmorpholine (5.8 mL, 52.72 mmol) and2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). Stirthe mixture for 1 h and add a solution of 4-aminomethyltetrahydropyran(6.6 g, 57.34 mmol) in dry THF (75 mL) by dropping funnel. Warm themixture to room temperature and stir for 3 h. Cool the mixture to 5° C.,add 1N HCl (250 mL) and partition the resulting solution with ethylacetate (250 mL). Extract the organic layer with aqueous saturatedsodium bicarbonate (250 mL), brine (250 mL), and dry over sodiumsulfate. Concentrate to give a foam, dissolve in minimum methylenechloride and add to a flash 65 M cartridge. Elute with 3:2 hexanes/ethylacetate to give the major product as a solid, filter from hexanes, anddry (20 mm Hg, 40° C.) to give the homogeneous white solid (20.5 g,85%); MS (ESI) m/z 467 (m+H).

EXAMPLE 2214-(3-Cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

Charge a 500 mL 3-neck roundbottom flask equipped with overhead stirrer,temperature probe, dropping funnel, and N₂ line with4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid (7.8 g, 21.1 mmol) inanhydrous THF (100 mL). Cool the solution and stir at 0° C. and addN-methylmorpholine (NMM, 2.4 mL, 21.8 mmol) and2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 3.7 g, 21.1 mmol). Stir themixture for 1 h at 0° C. and add a solution of 4-fluorobenzylamine (2.7mL, 23.6 mmol) in anhydrous THF (30 mL) over 10 minutes via droppingfunnel. Bring the resulting suspension to room temperature and stir for3 h. Cool the mixture to 0° C. and treat with 1N HCl (100 mL). Add ethylacetate (100 mL) and separate the layers. Dry the organic layer oversodium sulfate and concentrate to a residue which was held aside at thispoint.

Repeat the reaction exactly as outlined above using4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid (8.8 g, 23.82 mmol),NMM (2.7 mL, 24.5 mmol), CDMT (4.2 g, 23.9 mmol), 4-fluorobenzylamine(3.1 mL, 27.1 mmol) and anhydrous THF (160 mL). Following reaction andwork-up as previously described, obtain the crude organic residue(similar, albeit less pure) TLC profile (3:2 hexanes/ethyl acetate) tothat from the initial reaction. Independently chromatograph the twoorganic extracts (biotage 65M, 5% ethyl acetate in toluene) to providein both cases separation of the major component. Pool the appropriatefractions at this point and concentrate to a white foam. Dry the foam(20 mm Hg, 40° C.) to provide a white powder (14.6 g, 68%); MS (ESI) m/z477 (m+H). Dissolve 20 mg4-(3-cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide inisopropyl ether, though a small amount of oil remained at the bottom.Vigorously stir the sample until evaporation occurs and a white powderforms: onset of melting is 113° C.

EXAMPLE 222N-(5-Fluoro-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Make a 242.7 mg/mL solution ofN-(5-fluoro-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamidein methanol. Allow the solution to evaporate to dryness: onset ofmelting at 131° C.

EXAMPLE 223(N-(5-Fluoro-pyridin-2-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Add to a stirring mixture of 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid(5.0 g, 13.25 mmol) and 2-aminomethyl-5-fluoropyridine (dihydrochloride)(2.9 g, 14.57 mmol) in anhydrous methylene chloride (60 mL), EDCI (3.8g, 19.82 mmol) and 4-DMAP (6.0 g, 49.10 mmol). Stir the resultingsolution overnight at room temperature, concentrate to a paste, andpartition between ethyl acetate (100 mL), water (100 mL), and brine (100mL). Dry the organic layer over sodium sulfate and concentrate to anoil. Dissolve the oil in methylene chloride and add to a biotage 65cartridge. Elute with 1:1 ethyl acetate/hexanes to provide isolation ofthe pure 3(N-(5-Fluoro-pyridin-2-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamideas a solid, 5.7 g (89%): ¹H NMR (DMSO-d₆) δ 9.32 (t, J=5.9 Hz, 1H), 8.46(d, J=2.9 Hz, 1H), 8.20 (d, J=8.3 Hz, 2H), 8.12 (s, 1H), 8.03 (m, 3H),7.82 (d, J=7.8 Hz, 1H), 7.72 (d, J=6.8 Hz, 2H), 7.62 (dt, J=2.9, 8.8 Hz,1H), 7.50 (t, J=7.3 Hz, 2H), 7.39 (m, 4H), 4.50 (d, J=5.9 Hz, 2H); MS(ESI) m/z 486 (m+H).

EXAMPLE 224(N-(5-Fluoro-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide

Add to a stirring mixture of 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid(5.0 g, 13.25 mmol), and 2-aminomethyl-4-fluoropyridine (2.9 g, 14.57mmol) in anhydrous methylene chloride (60 mL) EDCI (3.8 g, 19.82 mmol)and 4-DMAP (6.0 g, 49.10 mmol). Stir the resulting solution overnight atroom temperature and concentrate to an oil. Partition the oil betweenethyl acetate (100 mL), water (100 mL), and brine (100 mL). Combine theaqueous layers and back-extract with methylene chloride (100 mL) and drythe organics over sodium sulfate. Concentrate to give an oil anddissolve in methylene chloride and add to a biotage 65 cartridge. Elutewith 3:2 ethyl acetate/hexanes gradually increasing to 4:1 ethylacetate/hexanes to give the major product as a foam which is found to behomogeneous 3(N-(5-Fluoro-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide5.6 g (87%); ¹H NMR (DMSO-d₆) δ 9.28 (t, J=5.9 Hz, 1H), 8.44 (d, J=2.9Hz, 1H), 8.39 (s, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.12 (s, 1H), 8.04 (d,J=8.3 Hz, 1H), 8.00 (d, J=8.3 Hz, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.72 (d,J=7.3 Hz, 2H), 7.60 (m, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.39 (m, 3H), 4.48(d, J=5.9 Hz, 2H); MS (ESI) m/z 486 (m+H).

EXAMPLE 226N-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide

Slowly add 3-phenyl-1H-pyrrolo[2,3-b]pyridine (178 mg, 0.915 mmol, 1.0eq) as a 2 ml DMF solution to a flask under N₂ containing potassiumtertbutoxide (108 mg, 0.961 mmol, 1.05 eq) in 1 ml DMF solution. Stirsolution for 5 minutes. Slowly add4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (300 mg, 0.915mmol, 1.0 eq) as a 3 ml DMF solution. Stir reaction for 18 hours at roomtemperature. Strip reaction of solvent and purify on silica gelchromatography to giveN-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide(82 mg, 18% yield). Mass Spectrum (m/e): 485.94 (MH+).

EXAMPLE 228N-(4-Fluoro-benzyl)-4-[3-(2-piperidin-1-yl-acetyl)-indole-1-sulfonyl]-benzamide

Slowly add 1-(1H-Indol-3-yl)-2-piperidin-1-yl-ethanone (199 mg, 0.821mmol, 1.0 eq) as a 2 ml DMF solution to a flask under N₂ containingsodium hydride (36 mg, 60 wt % on oil, 0.903 mmol, 1.1 eq) in 2 ml DMFsolution. Stir solution for 5 minutes. Slowly add4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (296 mg, 0.903mmol, 1.1 eq) as a 3 ml DMF solution. Stir reaction for 18 hours at roomtemperature. Strip reaction of solvent and purify on silica gelchromatography to giveN-(4-Fluoro-benzyl)-4-[3-(2-piperidin-1-yl-acetyl)-indole-1-sulfonyl]-benzamide(249 mg, 57% yield). Mass Spectrum (m/e): 534 (MH+).

EXAMPLE 2294-(3-Cyclohexyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

Add 4-Fluoro-benzylamine (72 mg, 0.574 mmol, 1.1 eq) followed bytriethylamine (343 mg, 0.472 ml, 3.39 mmol, 6.5 eq) to a CH₂CL₂ solution(8 ml) of 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.521mmol, 1 eq). Add benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (231 mg, 0.521 mmol, 1 eq) and stir at roomtemperature for 16 hours. Remove solvent on rotovap and purify crude bysilica gel chromatography to give4-(3-Cyclohexyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide (232mg, 99% yield). Mass Spectrum (m/e): 490.92 (MH+).

EXAMPLE 2304-(3-Cyclohexyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

Using a similar procedure as for4-(3-Cyclohexyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide to give275 mg (100% yield) of the title compound Mass Spectrum (m/e): 480.97(MH+).

EXAMPLE 2314-(3-Cyclohexyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-yl)-benzamide

Using a similar procedure as for4-(3-Cyclohexyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide to give198 mg (71% yield) of the title compound: Mass Spectrum (m/e): 466.94(MH+).

EXAMPLE 2324-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamide

Add a 2 ml CH₂Cl₂ solution of Tetrahydro-pyran-4-ylamine (62 mg, 0.0610mmol, 1.1 eq) and triethylamine (365 mg, 3.6 mmol, 6.5 eq) to a 2 mlCH₂Cl₂ solution of4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid. Addbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(245 mg, 0.555 mmol, 1.0 eq) and stir reaction at room temperature for18 hours. Remove volatiles on rotovap and purify by silica gelchromatography, followed by SCX ionic chromatography to give4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamide(240 mg, 89% yield). Mass Spectrum (m/e): 489.71 (MH+).

EXAMPLE 2334-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

Using a similar procedure as for4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamideusing C-(Tetrahydro-pyran-4-yl)-methylamine in place ofTetrahydro-pyran-4-ylamine to give4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-ylmethyl)-benzamide(280 mg, 100% yield). Mass Spectrum (m/e): 503.98 (MH+).

EXAMPLE 234N-(4-Fluoro-3-methoxy-benzyl)-4-(3-piperidin-1-yl-indole-1-sulfonyl)-benzamideHydrochloride

Add KotBu (211 mg, 1.88 mmol) to a solution of3-piperidin-1-yl-1H-indole (299 mg, 1.49 mmol) in dioxane (15 mL). Stirthe yellow solution at RT for 30 min then treat with4-(4-fluoro-3-methoxy-benzylcarbamoyl)-benzenesulfonyl chloride (560 mg,1.56 mmol). Stir the solution at RT for an additional 2 h, then dilutewith EtOAc (50 mL) and wash with satd NaHCO₃ (25 mL). Remove the organicphase and extract the aqueous layer with additional EtOAc (50 mL).Combine the organic solutions, dry over Na₂SO₄, filter, and concentrate.Purify the crude material by flash chromatography (3×) using anoversized silica column and a gradient of 100% hexanes to 40%EtOAc/hexanes. Concentrate fractions containing pure material thenredissolve in CH₂Cl₂ (10 mL) and treat with 4M HCl/dioxane (0.5 mL).Filter the off-white precipitate and dry under vacuum to give the titlecompound as a white powder (417 mg). MS (ES⁺) 522.1 (M+1)⁺, (ES⁻) 520.2(M−1)⁻. ¹H NMR (400 MHz, DMSO-d₆): δ 9.19 (m, 1H), 8.03 (d, 2H, J=8.4),7.97 (m, 1H), 7.95 (d, 2H, J=8.4), 7.61 (d, 1H, J=7.5), 7.37 (t, 1H,J=7.6), 7.26 (t, 2H, J=7.5), 7.06-7.13 (m, 2H), 6.81 (m, 1H), 6.12 (brs, 1H), 4.39 (d, 2H, J=5.7), 3.78 (s, 3H), 3.06 (s, 4H), 1.72 (s, 4H),1.56 (s, 2H).

EXAMPLE 2404-{[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl}-N,N-dimethyl-benzamide

Combine 4-{[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl}-benzoicacid (0.489 mmole) with dimethylamine (0.587 mmole), and EDC (0.733mmole) in 5 ml of dichloromethane and stir for 15 hrs. Dilute □eactionand wash with 1 N HCl. Dry organic layer over MgSO₄ and concentrate.Purify the residue via column chromatography with a mixture of ethylacetate and dichloromethane to isolate 0.040 g (15.2%) of the titlecompound: MSES+ 537.95; MSES−536.08.

GENERAL EXAMPLE 241 EDC Coupling

Combine the amine (0.809 mmole), benzoic acid, for example,4-(3-Cyclopentyl-indazole-1-sulfonyl)-benzoic acid (0.539 mmole), EDC(0.809 mmole) in 5 ml of dichloromethane and stir for 15 hrs. Dilute thereaction mixture and wash with 1 N HCl. Dry organic material over MgSO₄and concentrate. Purify the residue via column chromatography using amixture of ethyl acetate and dichloromethane.

Prepare the following compounds by essentially following General Example241.

Ex Name of the amine MS ES+/ % No Structure and name of final cmpdstarting material MS ES− yield 242

4-(3-Cyclopentyl-indazole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide4-Fluoro-benzylamine 478.30/476.50 60 243

4-(3-Cyclopentyl-indazole-1-sulfonyl)-N-(tetrahydro-pyran-4-yl)-benzamideTetrahydro-pyran-4-ylamine 454.00/452.20 46 244

4-(3-Cyclopentyl-indazole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamideC-(Tetrahydro-pyran-4-yl)-methylamine 468.00/466.20 38 245

4-(3-Cyclopentyl-indazole-1-sulfonyl)-N-isobutyl-benzamide Isobutylamine426.00/424.20 47 246

4-(3-Cyclopentyl-indazole-1-sulfonyl)-N-cyclopropylmethyl-benzamideC-Cyclopropyl-methylamine 424.00/422.20 47 247

4-{[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl}-N,N,-dimethyl-benzamideDimethylamine 537.95/536.08 15.2

GENERAL EXAMPLE 248 Bop Couplings

Combine the amine (0.525 mmole), BOP (0.421 mmole), Triethylamine (1.05mmole), and the appropriate benzoic acid (0.350 mmole) and stir in 5 mlof dichloromethane for 4 hrs. Concentrate the reaction and purify vialcolumn chromatography using a mixture of ethyl acetate anddichloromethane.

Prepare the following compounds by essentially following General Example248.

Ex Name of the amine starting MS ES+/ % No Structure and name of finalcmpd material MS ES− yield 249

(R)-C-(Tetrahydro-furan-2-yl)-methylamine 454.00/452.20 80 250

(S)-C-(Tetrahydro-furan-2-yl)-methylamine 454.00/452.10 75 252

C-(Tetrahydro-pyran-2-yl)-methylamine 483.00/481.10 10.9

GENERAL EXAMPLE 253 EDC-DMAP

Combine the amine (0.300 mmole), the appropriate benzoic acid (0.300mmole), DMAP (0.300 mmole), and EDC (0.450 mmole) in 5 ml ofdichloromethane and stir until reaction is complete. Dilute the reactionand wash with 1 N HCl. Dry organic layer over MgSO₄ and concentrate.Purify the residue via column chromatography with a mixture of ethylacetate and dichloromethane.

Prepare the following compounds by essentially following General Example253.

Ex Name of the amine MS ES+/ % No Structure and name of final cmpdstarting material MS ES− yield 254

(R)-1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine 539.97/538.23 52 254a

(S)-1-(4-Fluoro-phenyl)-pyrrolidin-3-ylamine 52 255

Azetidin-3-yl-(4-fluoro-phenyl)-amine 525.96 12.4 256

C-(Tetrahydro-pyran-2-yl)-methylamine 474.99 19 257

C-(Tetrahydro-pyran-2-yl)-methylamine 466.94/465.10 81.2

EXAMPLE 257a4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-2-ylmethyl)-benzamideIsomer 1

Separate the racemate of4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-2-ylmethyl)-benzamideon a 8×29 cm Chiralpak AD column with 100% 3A (anhydrous ethanol) usingas the mobile phase, 300 ml/min flow rate, and UV detection at 220 nm.Analyze on a 4.6×150 mm Chiralpak AD-H column with 100% 3A as the mobilephase, 0.6 ml/min flow rate, and UV detection at 219 nm to give theisolation of isomer 1 which elutes at 12.6 min MS ES+ 466.98 MS ES−465.07.

EXAMPLE 257b4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-2-ylmethyl)-benzamideIsomer 2

Separate the racemate of4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-2-ylmethyl)-benzamideon a 8×29 cm Chiralpak AD column with 100% 3A (anhydrous ethanol) as themobile phase, 300 ml/min flow rate, and UV detection at 220 nm. Analyzeon a 4.6×150 mm Chiralpak AD-H column with 100% 3A as the mobile phase,0.6 ml/min flow rate, and UV detection at 219 nm to give the isolationof isomer 2 MS ES+ 467.0 MS ES− 465.1 elutes at 18.8 min.

EXAMPLE 2594-(3-Cyclopentyl-indole-1-sulfonyl)-N-pyridin-3ylmethyl-benzamide

Add to a stirring mixture of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoicacid (0.188 g, 0.50 m mol), PyBOP (0.0.288 g, 0.50 m mol), and3-amino-pyridine (0.063 g, 0.59 mmol) in dry CH₂Cl₂ (10 mL) under N₂,Hunigs base (0.148 g, 0.200 mL, 1.11 m mol.). Stir the reaction isovernight at ambient temperature and evaporate on the rotary evaporator.Chromatograph the residue on the ISCO system using a 40 g column and ahexane-EtOAc gradient system (0-100%) to give 0.048 g of the titlecompound as white foam: Mass spectrum (m/e) (M+H) 460.1697; found460.1681.

EXAMPLE 2604-(3-Cyclopentylindole-1-sulfonyl)-N—[(R)-1-(tetrahydrofuran-2-yl)methyl]benzamide

Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 98mg, 0.51 mmol, 1.5 equiv) and 4-(dimethylamino)pyridine (DMAP; 70 mg,0.57 mmol, 1.7 equiv) to a solution of4-(3-cyclopentylindole-1-sulfonyl)benzoic acid (126 mg, 0.341 mmol, 1equiv) and (R)-(−)-tetrahydrofurfurylamine (Aldrich; 140 μL, 140 mg, 1.4mmol, 4.0 equiv) in anhydr CH₂Cl₂ (1 mL). After stirring 16 h, transferthe reaction solution to a column of silica gel (80 mm×20 mm dia.) andelute (10-45% EtOAc/hex) to give 24 mg (16%) of4-(3-cyclopentylindole-1-sulfonyl)-N—[(R)-1-(tetrahydrofuran-2-yl)methyl]benzamideas a white foam. MS (m/e): 452.96 (M+1); 451.14 (M−1).

EXAMPLE 2614-(3-Phenylindole-1-sulfonyl)-N-(tetrahydrofuran-3-ylmethyl)benzamide

Add benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (2.2 g, 5.0 mmol, 1.5 equiv) to a solution of4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (1.23 g, 3.26 mmol, 1equiv), (tetrahydro-furan-3-yl)-methylamine (331 mg, 3.27 mmol, 1.0equiv), and triethylamine (2.3 mL, 1.7 g, 17 mmol, 5.0 equiv) in anhydrCH₂Cl₂ (12 mL). After 1 h, rotary evaporate the reaction solution andtransfer the resultant residue to a column of silica gel (235 mm×35 mmdia.) and elute (50-90% EtOAc/hex). This yields 486 mg (32.4%) ofrac-4-(3-phenyl-indole-1-sulfonyl)-N-(tetrahydro-furan-3-ylmethyl)-benzamideas a yellow foam. MS (m/e): 460.96 (M+1); 459.04 (M−1).

EXAMPLE 261a4-(3-Phenylindole-1-sulfonyl)-N-(tetrahydrofuran-3-ylmethyl)benzamideisomer 1

Separate the enantiomers ofrac-4-(3-phenyl-indole-1-sulfonyl)-N-(tetrahydro-furan-3-ylmethyl)-benzamide(470 mg) using a Chiralpak AD-H column (4.6×150 mm) with 95% EtOH/MeOHat 0.6 mL/min. Collect peak at 9.8 min followed by rotary evaporation togive 154 mg (32.8%) of4-(3-phenylindole-1-sulfonyl)-N-(tetrahydrofuran-3-ylmethyl)benzamideisomer 1. MS (m/e): 460.96 (M+1); 459.03 (M−1).

EXAMPLE 261b4-(3-Phenylindole-1-sulfonyl)-N-(tetrahydrofuran-3-ylmethyl)benzamideisomer 2

Separate the enantiomers ofrac-4-(3-phenyl-indole-1-sulfonyl)-N-(tetrahydro-furan-3-ylmethyl)-benzamide(470 mg) using a Chiralpak AD-H column (4.6×150 mm) with 95% EtOH/MeOHat 0.6 mL/min. Collect peak at 12.6 min followed by rotary evaporationto give 156 mg (33.2%) of4-(3-phenylindole-1-sulfonyl)-N-(tetrahydrofuran-3-ylmethyl)benzamideisomer 2. MS (m/e): 460.96 (M+1); 459.04 (M−1).

EXAMPLE 265

(3-Hydroxymethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]methanone

Dissolve azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (300 mg,1.50 mmol.) in THF (5.0 mL) and treat with lithium aluminum hydride(1.0M in ether, 3.0 mL, 3.0 mmol). Stir for 18 hours, quench with 3.0 mLof 1.0M NaOH, dilute with ether, filter through celite and evaporate.Treat the resulting 3-hydroxymethyl-azetidine-1-carboxylic acidtert-butyl ester with 10 mL of trifluoroacetic acid for 20 minutes anevaporate. Use this material without further purification. Combine4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (100 mg, 0.26 mmol) and theresulting azetidin-3-yl-methanol in dichloromethane (1.0 mL) andtriethylamine (0.100 mL, 0.717 mmol, excess) and addbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate(BOP Reagent) (150 mg, 0.33 mmol, excess) at room temperature. Stir for30 minutes, evaporate and load entire reaction directly onto pre-packedsilica gel column and purify by flash column chromatography(EtOAc/Hexanes) to give 41 mg of(3-Hydroxymethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanoneas a white solid (35%). LRMS: MH+ 447.2.

EXAMPLE 2664-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide

In a 12 L RBF, charge 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid(400 g, 1.084 mol) and THF (3.6 L) and cool the solution to 5° C., andadd 4-methylmorpholine (121 g, 1.192 mol). Add CDMT (209 g, 1.192 mol)over a 5 minute period and stir for 1 hour at 5° C. Add a solution of4-aminomethyltetrahydropyran (150 g, 1.300 mol) and THF (500 ml)drop-wise over a 1 hour period at 5° C. Remove the cooling bath and stirthe reaction for 75 minutes. Cool the solution to 10° C. and quench with1N HCl (4 L). Add ethyl acetate (2.5 L), DI water (2 L) and back extractthe aqueous layer with ethyl acetate (2 L). Wash the organic layers withsaturated sodium bicarbonate (3 L), brine (3 L), dry over sodiumsulfate, filter and concentrate under vacuum to give 575 g of anoil/foam. Purify the crude material by silica plug filtration and slurryin methanol (2 L) for 2 hours. Cool the slurry to 5° C., stir for 2hours, filter, rinse with methanol (0.5 L) and dry at 45° C. in a vacuumoven to provide 485 g of a white solid (yield=96%) of the title compounddemonstrating two melts one at 136-138° C. and a second at 153-155° C.

EXAMPLE 2674-(3-Cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

In a 22 L RBF, charge 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid(435 g, 1.177 mol) and THF (4 L). and cool the solution to 5° C., andadd 4-methylmorpholine (131 g, 1.295 mol). Add CDMT (227 g, 1.295 mol)in one portion and stir for 1 hour at 5° C. Add a solution of4-fluorobenzylamine (162 g, 1.295 mol) and THF (500 ml) drop-wise over a1 hour period at 5° C. Remove the cooling bath and stir the reaction wasfor 120 minutes. Cool the solution to 10° C. and quench with 1N HCl (4L). Add ethyl acetate (3 L), DI water (3 L) and back extract the aqueouslayer with ethyl acetate (3 L). Wash the organic layers with saturatedsodium bicarbonate (3 L), brine (3 L), dry over sodium sulfate, filterand concentrate under vacuum to give 575 g of an amber oil/foam. Purifythe crude material by silica plug filtration and slurry in methanol (2L) for 17 hours. Cool the slurry to 5° C., stir for 1 hour, filter,rinse with methanol (0.75 L) and dry at 45° C. in a vacuum oven toprovide 450 g of a white solid (yield=80.2%) of the title compoundhaving a single melt ranging from 118° C. to 121° C.; 1H NMR (DMSO) d9.2 (t, 1H), 8.1 (m, 2H), 7.95 (m, 2H), 7.9 (d, 1H), 7.6 (d, 1H), 7.5(s, 1H), 7.3 (m, 4H), 7.1 (t, 2H), 4.4 (dd, 2H), 3.1 (t, 1H), 2.05 (m,2H), 1.7 (m, 6H). % Theory C, 68.0484; H, 5.2876; N, 5.8781. % Found C,68.01; H, 5.13; N, 5.88.

EXAMPLE 2684-(3-Cyclopentyl-indole-1-sulfonyl)-N-pyridin-3yl-methyl-benzamide

Stir a mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid(0.188 g, 0.50 mmol), PyBOP (0.0.288 g, 0.50 m mol), and3-amino-pyridine (0.063 g, 0.59 mmol) in dry CH₂Cl₂ (10 mL) under N₂ addHunigs base (0.148 g, 0.200 mL, 1.11 mmol). Stir overnight the reactionat ambient temperature and evaporate on the rotary evaporator.Chromatograph the residue on the ISCO using a 40 g column and ahexane-EtOAc gradient system (0-100%) to give 0.048 g of the titlecompound as a white foam. Mass spectrum (m/e) (M+H) 460.1697; found460.1681.

EXAMPLE 269 4-(3-Cyclopentyl-indole-1-sulfonyl)-n-isobutyl-benzamide

Stir to a mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid(0.163 g, 0.44 m mol), PyBOP (0.226 g, 0.51 mmol), and isobutylamine(0.038 g, 0.52 mmol) in dry CH₂Cl₂ (10 mL) under N₂ add Hunigs base(0.148 g, 0.11 mmol). Stir the reaction overnight at ambient temperatureand evaporate on the rotary evaporator. Chromatograph the residue on theISCO using a 40 g column and a hexane-EtOAc gradient system (0-100%) togive 0.10 g of the title compound as a white foam. Mass spectrum (m/e)(M+H) 425.1899; found 460.1925.

EXAMPLE 270N-(4-Fluoro-benzyl)-4-(3-isopropyl-indole-1-sulfonyl)-benzamide

Stir a mixture of 3-isopropyl indole in dry DMF (20 ml) under N₂ addpotassium t-butoxide 1.0 M (1.2 ml, 1.2 mmol) dropwise. Stir theresulting solution for 30 minutes at ambient temperature. Add4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.360 g, 1.1mmol) portionwise and stir the resulting mixture overnight. Pour thereaction mixture into a mixture of EtOAc-H₂O. Separate the EtOAc layer,extract with H₂O wash with brine and dry (MgSO₄). Filter and evaporateto give the crude product. Chromatograph on the ISCO eluting withhexane-EtOAc to give a white solid (0.150 g). Mass spectrum (m/e) (M+H)451.1492; found 451.1488.

EXAMPLE 271N-Cyclopropylmethyl-4-(3-isopropyl-indole-1-sulfonyl)-benzamide

Stir mixture of 4-(3-isopropyl-indole-1-sulfonyl)-benzoic acid (0.181 g,0.53 mmol), PyBOP (0.243 g, 0.55 mmol) and cyclopropylmethyl amine(0.064 g, 0.59 mmol) in CH₂Cl₂ (20 mL) add Hunigs base (0.28 mL, 1.62mmol) under N₂. Stir the resulting mixture overnight at ambienttemperature. Extract the reaction with H₂O, wash with brine dry (MgSO₄),filter, evaporate and chromatograph using hexane-EtOAc (0-100%) to give0.183 g of the title compound as an off white solid: Mass spectrum (m/e)(M+H) 397.1593; found 397.1586.

EXAMPLE 2724-(3-Cyclopentyl-2,3-dihydro-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide

Add 4-(3-cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide(0.152 g, 0.319 mmol) portionwise to a stirring mixture of NaCNBH₃(0.096 g, 1.52 mmol) in TFA at 0 to 5° C. under N₂. Stir the mixture for15 minutes at 0-5° C., allow to warm to ambient temperature and add anadditional 0.096 g NaCNBH₃. Stir the resulting yellow solution for 2 hat ambient temperature, dilute with H₂O (13.0 mL) and stir overnight.Pour the reaction mixture is into EtOAc (100 mL). Separate the EtOAc,extract with H₂O, 5% NaHCO₃ and wash with brine. Separate the EtOAc, dry(MgSO₄), filter and evaporate giving a glass. Chromatograph on thechromatotron eluting with EtOAc-hexane 3:7 to give 0.060 g of the titlecompound: Mass spectrum (m/e) (M+H) 479.1805; found 479.1788.

EXAMPLE 273N-(4-Fluoro-benzyl)-4-(3-methyl-2,3-dihydro-indole-1-sulfonyl)-benzamide

Add N-(4-Fluoro-benzyl)-4-(3-methyl-indole-1-sulfonyl)-benzamide (0.106g, 0.25 mmol) portionwise to a stirring mixture of NaCNBH₃ (0.074 g, 1.2mmol, in TFA (5.0 mL) at 0 to 5° C. under N₂. Stir the mixture for 15minutes at 0-5° C., allow to warm to ambient temperature and stir for 1h. add NaCNBH₃ (0.074 g, 1.2 mmol) and stir the reaction is for 2 hdilute with H₂O (13.0 mL) and work up as described in the above example.Chromatograph and elute with EtOAc-hexane (0-50%) to give 0.075 g of thetitle compound: Mass spectrum (m/e) (M+H) 425.1335; found 425.1341.

EXAMPLE 274N-(4-Fluoro-benzyl)-4-(3-phenyl-2,3-dihydro-indole-1-sulfonyl)-benzamide

Stir 3-phenyl-2,3-dihydro-1H indole (0.233 g, 1.19 mmol),4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (1 equiv.), Et₃N(0.50 mL, 0.36 g, 3.57 mmol), DMA (0.015 g, 0.123 mmol) in CH₂Cl₂ (45mL) overnight under N₂. Dilute the CH₂Cl₂ to 150 mL and pour into asaturated solution of NaHCO₃ (50 mL) and stir for 15 minutes. Separatethe organic layer and wash with H₂O (100 mL), extract with 1N HCl (2×75mL), wash with brine, separate and dry (MgSO₄). Filter and evaporatefollowed by chromatography on the ISCO using a 40 g silica gel columnand elute with EtOAc-hexane 90-100%) to give 0.33 g of the racemiccompound.

EXAMPLE 274aN-(4-Fluoro-benzyl)-4-(3-phenyl-2,3-dihydro-indole-1-sulfonyl)-benzamideIsomer 1

SeparateN-(4-Fluoro-benzyl)-4-(3-phenyl-2,3-dihydro-indole-1-sulfonyl)-benzamidevia chromatograph separation on chiracel OD (column 90.46×25 cm)(EtOAc-hexane 90-100%) 1.0 mL/min to give (isomer 1) (0.60 g) retentiontime 5.45 nm in

EXAMPLE 274bN-(4-Fluoro-benzyl)-4-(3-phenyl-2,3-dihydro-indole-1-sulfonyl)-benzamideIsomer 2

Continue to separate Example 274a via chromatograph separation onchiracel OD (column 90.46×25 cm) (EtOAc-hexane 90-100%) 1.0 mL/min togive (isomer 2) (0.61 g) retention time 7.21 min.

EXAMPLE 2754-[3-(3-Cyano-phenyl)-indole-1-sulfonyl]-N-(4-fluoro-benzyl)-benzamide

StirN-(4-Fluoro-benzyl)-4-{3-(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2yl)-indole-1-sulfonyl}-benzamide(0.267 g, 0.50 mmol), 3-bromobenzonitrile (0.160 g, 0.55 mmol),PdCl₂(dppf).CH₂Cl₂ (0.032 g, 0.039 mmol) and 2M Na₂CO₃ (0.50 mL, 1.0mmol) and heat in dioxane (20 mL) at 81° C. under N₂ for 6 h.Concentrate the reaction and chromatograph the residue on the ISCO usinga 12 g silica gel column and eluting with hexane-EtOAc (0-100%) to givethe title compound as a light tan foam 0.100 g Mass spectrum (m/e) (4+H)510.1288; found 510.1283.

EXAMPLE 276N-(4-Fluoro-benzyl)-4-(3-thiazol-2-yl-indole-1-sulfonyl)-benzamide

StirN-(4-Fluoro-benzyl)-4-{3-(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2yl)-indole-1-sulfonyl}-benzamide(0.267 g, 0.50 mmol), 2-bromothiazole (0.090 g, 0.55 mmol),PdCl₂(dppf).CH₂Cl₂ (0.032 g, 0.039 mmol) and 2M Na₂CO₃ (0.25 mL, 0.50mmol) and heat in dioxane (20 mL) at 99° C. under N₂ for 14 h.Concentrate the reaction mixture to dryness and chromatograph theresidue on the ISCO, using a 12 g silica gel column and eluting withhexane-EtOAc (5-100%) to give the title compound as a white solid. Massspectrum (m/e) (M+H) 492.0852; found 492.0848.

EXAMPLE 2774-(3-Cyclopentyl-indole-1-sulfonyl)-N-(5-fluoro-pyridin-2-yl-methyl)-benzamide

Stir mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid (0.767g, 0.21 m mol), C-(5-fluoro-pyridin-2yl)-methylamine (0.041 g, 0.25mmol), and EDC (0.063 g, 0.33 mmol) in dry CH₂Cl₂ (15 mL) under N₂ andadd DMAP (0.061 g, 0.50 mmol.). Stir the resulting mixture at ambienttemperature for 72 h. Dilute the reaction mixture to 50 mL with CH₂Cl₂,wash with H₂O, 1N NaOH, and brine sequentially. Dry the organic layer(MgSO₄), filter and evaporate to give 0.189 g of crude product.Chromatograph on the ISCO using a 12 g column and eluting withHexane-EtOAc (0-100%) to gives the title compound 0.60 g as a foam:

Calcd. for: C₂₆H₂₄FN₃O₃; C, 65.39; H, 5.066; N, 8.79. Found: C, 65.50;H, 5.26; N, 8.61.

EXAMPLE CB1 and CB2 GTPγ³⁵S Binding Assays

CB1 and CB2 GTPγ³⁵S binding assays were run essentially as described inDeLapp et al. in pH 7.4 buffer containing 20 mM HEPES, 100 mM NaCl and 5mM MgCl₂ (NaCl was omitted from rat brain membrane assay) in a finalvolume of 200 μl in 96-well Costar plates at 25° C. 100 μl of membranepreparation (25 μg protein per well for CB1 or CB2 Sf9 cell membranes,15-18 μg per well for rat cerebellar membranes) containing theappropriate concentration of GDP (1 μM GDP for CB1 Sf9 cell membranes,0.05 μM for CB2 Sf9 cell membranes, 25 μM GDP for rat cerebellarmembrane assays) was added to each well followed by the addition of 50μl of buffer±test compounds or controls and then the plates wereincubated for 30 minutes. Next 50 μl of GTPγ³⁵S was added to a finalconcentration of 400 pM in each well and the plates were incubated foranother 30 minutes. After that, 20 μl of 0.27% Nonidet P-40 was addedwith a 30 minute incubation before the addition of 20 μl/well of a 1/400to 1/100 final dilution anti-GαI(1-3) antibody (rabbit antibody toBSA-conjugated peptide KNNLKECGLY) with a 60 minute incubation. 50 μl ofSPA beads (PVT; anti-rabbit antibody) resuspended in 20 mL assay bufferwere then added to each well. After 180 min, plates are centrifuged at900 g for 10 min and G-protein bound radioactivity was measured using aWallac plate counter.

DeLapp N W. McKinzie J H. Sawyer B D. Vandergriff A. Falcone J. McClureD. Felder C C. Determination of [³⁵S]guanosine-5′-O-(3-thio)triphosphatebinding mediated by cholinergic muscarinic receptors in membranes fromChinese hamster ovary cells and rat striatum using an anti-G proteinscintillation proximity assay. [Journal Article] Journal of Pharmacology& Experimental Therapeutics. 289(2):946-55, 1999 May.

In this test, the IC 50 of the compounds of formula (I) is less than orequal to 5 μM.

The utilities of the present compounds in treating or preventingdiseases or disorders may be demonstrated in animal disease models thathave been reported in the literature. The following are examples of suchanimal disease models: a) suppression of food intake and resultantweight loss in rats (Life Sciences 1998, 63, 113-117); b) reduction ofsweet food intake in marmosets (Behavioural Pharm. 1998, 9, 179-191); c)reduction of sucrose and ethanol intake in mice (Psychopharm. 1997, 132,104-106); d) increased motor activity and place conditioning in rats(Psychopharm. 1998, 135, 324-332; Psychopharmacol 2000, 151: 25-30); e)spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277,586-594); and f) reduction in opiate self-administration in mice (Sci.1999, 283, 401-404).

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well-known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range lie within the range of from about 0.001 mg to about 100 mgper kg body weight of a mammal, preferably 0.01 mg to about 50 mg perkg, and most preferably 0.1 to 10 mg per kg, in single or divided doses.On the other hand, it may be necessary to use dosages outside theselimits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg to about 25 mg(preferably from 0.01 mg to about 1 mg) of a compound of Formula I perkg of body weight per day and for cytoprotective use from about 0.1 mgto about 100 mg (preferably from about 1 mg to about 100 mg and morepreferably from about 1 mg to about 10 mg) of a compound of Formula Iper kg of body weight per day.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 100 mg of a compound ofFormula I per day, preferably from about 0.1 mg to about 10 mg per day.For oral administration, the compositions are preferably provided in theform of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05,0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0 or1000.0 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient, preferably present in pharmaceuticallyeffective amounts, and the inert ingredient(s) (pharmaceuticallyacceptable excipients) that make up the carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of Formula I andpharmaceutically acceptable excipients.

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, suppositories and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. In particular,the term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic bases or acids and organic bases or acids. The compound may bepresent in crystalline form or may be incorporated into thepharmaceutical composition as an amorphous solid. Alternatively, thecompound may be rendered partially or totally amorphous by themanufacturing process.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), ornasal administration, although the most suitable route in any given casewill depend on the nature and severity of the conditions being treatedand on the nature of the active ingredient. They may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulizers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery systems for inhalation are metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of a compound of Formula I in suitable propellants, such asfluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol,which may be formulated as a dry powder of a compound of Formula I withor without additional excipients.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, ointments, lotions, dustingpowders, and the like. Topical preparations containing the active drugcomponent can be admixed with a variety of carrier materials well knownin the art such as, e.g., alcohols, aloe vera gel, allantoin, glycerine,vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and thelike. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

The compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylasparamidepheon, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with or solubilization in apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral (including intravenous). In preparing thecompositions for oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, simple oils,fractionated or chemically-modified glycerides,polyoxyethylene-polyoxypropylene co-polymers, alcohols, surface activeagents, flavoring agents, preservatives, coloring agents and the like inthe case of oral liquid preparations, such as, for example, suspensions,elixirs and solutions; or carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents and the like in the case of oral solidpreparations such as, for example, powders, capsules and tablets, withthe solid oral preparations being preferred over the liquidpreparations. The carrier may possess special properties for controllingor modifying the release and subsequent absorption profile of the drugsubstance, said properties including but not limited toself-emulsification, or controlled disintegration, dissolution orsolubilization in vivo. Because of their ease of administration, tabletsand capsules represent the most advantageous oral dosage unit form inwhich case solid pharmaceutical carriers are obviously employed. Ifdesired, tablets may be coated by standard aqueous or nonaqueoustechniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Hard or soft gelatin capsules may be prepared by fillingeither with dry powder or granule formulations or by filling with aliquid formulation compatible with the capsule shell. Desirably, eachtablet contains from 0.01 to 500 mg, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175,180, 200, 225, and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Andeach cachet or capsule contains from about 0.01 to 500 mg, particularly0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0,75, 100, 125, 150, 175, 180, 200, 225, and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration and/or the characteristics of the dosageform (i.e., modified release), the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagemay be correspondingly larger for the less frequent administration.

When administered via transdermal routes or through a continualintravenous solution, the dosage administration will, of course, becontinuous rather than intermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

Injectable Suspension (I.M.) mg/mL Compound of Formula I 10Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkoniumchloride 1.0 Water for injection to a total volume of 1 mL

Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415Povidone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500

Capsule (Dry Fill) mg/capsule Compound of Formula I 25 Lactose Powder573.5 Magnesium Stearate 1.5 600

Capsule (Liquid Fill) mg/capsule Compound of Formula I 25 Peanut oil 575600

Capsule (Semi-solid Fill, self-emulsifying) mg/capsule Compound ofFormula I 25 Gelucire 44/14 575 600

Capsule (Liquid Fill, Self-Emulsifying) mg/capsule Compound of Formula 125 Sesame Oil 125 Cremophor RH40 300 Peceol 150 600

Aerosol Per canister Compound of Formula I 24 mg Lecithin, NF Liq. Conc.1.2 mg Trichlorofluoromethane, NF 4.025 g Dichlorodifluoromethane, NF12.15 g

The above dosage form examples are representative. The amount of thecompound present in compositions is such that a suitable dosage will beobtained. Preferred compositions and preparations according to thepresent invention may be determined by a person skilled in the art.

1-45. (canceled)
 46. A method for treating a condition which is treatable by reducing CB-1 receptor stimulation, comprising administering to a mammal in need thereof an effective amount of a compound selected from the group consisting of: N-(4-Fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide, N-(5-Fluoro-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide, 4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide, N-(4-Fluoro-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide, N-Cyclopropylmethyl-4-(3-phenyl-indole-1-sulfonyl)-benzamide, 4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-yl)-benzamide, and 4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide.
 47. The method of claim 46, wherein the condition is associated with excessive food intake.
 48. The method of claim 46, wherein the condition is obesity.
 49. A method of ameliorating weight gain comprising administering to a mammal in need thereof an effective amount of a compound selected from the group consisting of: N-(4-Fluoro-benzyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide, N-(5-Fluoro-pyridin-3-ylmethyl)-4-(3-phenyl-indole-1-sulfonyl)-benzamide, 4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(4-fluoro-benzyl)-benzamide, N-(4-Fluoro-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-indole-1-sulfonyl]-benzamide, N-Cyclopropylmethyl-4-(3-phenyl-indole-1-sulfonyl)-benzamide, 4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-yl)-benzamide, and 4-(3-Cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide. 